Delivery of radiation by column and generating a treatment plan therefor

ABSTRACT

An example method of treating a target using particle beam includes directing the particle beam along a path at least part-way through the target, and controlling an energy of the particle beam while the particle beam is directed along the path so that the particle beam treats at least interior portions of the target that are located along the path. While the particle beam is directed along the path, the particle beam delivers a dose of radiation to the target that exceeds one (1) Gray-per-second for a duration of less than five (5) seconds. A treatment plan may be generated to perform the method.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 17/712,313, which was filed on Apr. 4, 2022, and which is titled “Delivery Of Radiation By Column and Treatment Plan Therefor”. U.S. patent application Ser. No. 17/712,313 is incorporated herein by reference. U.S. patent application Ser. No. 17/712,313 is a continuation, and claims priority to, U.S. patent application Ser. No. 16/811,130, which was filed on Mar. 6, 2020. U.S. patent application Ser. No. 16/811,130 is incorporated herein by reference. U.S. patent application Ser. No. 16/811,130 and, therefore this application, claims priority to, and the benefit of, U.S. Provisional Patent Application No. 62/815,721, which was filed Mar. 8, 2019, and which is titled “Delivery Of Radiation By Column”. U.S. patent application Ser. No. 16/811,130 and, therefore this application, claims priority to, and the benefit, of U.S. Provisional Patent Application No. 62/853,387, which was filed on May 28, 2019, and which is titled “Energy Degrader Including Boron Carbide”. U.S. patent application Ser. No. 16/811,130 and, therefore this application, claims priority to, and the benefit, of U.S. Provisional Patent Application No. 62/889,825, which was filed on Aug. 21, 2019, and which is titled “Generating A Treatment Plan”. U.S. patent application Ser. No. 16/811,130 and, therefore this application, claims priority to, and the benefit, of U.S. Provisional Patent Application No. 62/889,861, which was filed on Aug. 21, 2019, and which is titled “Collimator For A Particle Therapy System”. The contents of U.S. Provisional Patent Applications Nos. 62/815,721, 62/853,387, 62/889,825, and 62/889,861 are incorporated herein by reference.

TECHNICAL FIELD

This disclosure relates generally to a particle therapy system that delivers doses of radiation by column and to generating a treatment plan therefor.

BACKGROUND

Particle therapy systems use an accelerator to generate a particle beam for treating afflictions, such as tumors. In operation, particles are accelerated in orbits inside a cavity in the presence of a magnetic field and are removed from the cavity through an extraction channel. A magnetic field regenerator generates a magnetic field bump near the outside of the cavity to distort the pitch and angle of some orbits so that they move towards, and eventually into, the extraction channel. A beam, comprised of the particles, exits the extraction channel.

A scanning system is down-beam of the extraction channel. In this example, down-beam suggests closer to an irradiation target relative to the extraction channel. The scanning system moves the particle beam relative to the irradiation target to expose various parts of the irradiation target to the particle beam. For example, to treat a tumor, the particle beam may be scanned over different parts of the tumor to expose the different parts to radiation.

Particle therapy systems typically operate in accordance with a treatment plan. A treatment plan may specify, among other things, doses of radiation to be delivered to the patient by the particle therapy system.

SUMMARY

An example method of treating a target using a particle beam includes directing the particle beam along a path at least part-way through the target, and controlling an energy of the particle beam while the particle beam is directed along the path so that the particle beam treats at least interior portions of the target that are located along the path. While the particle beam is directed along the path, the particle beam delivers a dose of radiation to the target that exceeds one (1) Gray-per-second for a duration of less than five (5) seconds. The example method may include one or more of the following features, either alone or in combination.

Directing and controlling may be performed for each of multiple micro-volumes of the target. Controlling the energy of the particle beam may include moving one or more energy-absorbing plates into or out of the path of the particle beam between the target and a source of the particle beam. Moving the one or more energy-absorbing plates into or out of the path of the particle beam may be performed while the particle beam is directed along the path. Moving the one or more energy-absorbing plates into or out of the path of the particle beam may include moving multiple energy-absorbing plates sequentially into the path of the particle beam. Moving the one or more energy-absorbing plates into or out of the path of the particle beam may include moving multiple energy-absorbing plates sequentially out of the path of the particle beam. An energy-absorbing plate among the one or more energy-absorbing plates may include a linear motor that is controllable to move the energy-absorbing plate into or out of the path of the particle beam. Each of the one or more energy-absorbing plates may be movable into or out of the path of the particle beam in a duration of one hundred (100) milliseconds or less. Each of the one or more energy-absorbing plates may be movable into or out of the path of the particle beam in a duration of fifty (50) milliseconds or less. Each of the one or more energy-absorbing plates may be movable into or out of the path of the particle beam in a duration of ten (10) milliseconds or less. Moving the one or more energy-absorbing plates into or out of the path of the particle beam may include controlling a first plate among the one or more energy-absorbing plates to move during passage of the particle beam through the one or more energy-absorbing plates to the target. The first plate being may be configured and controllable to move across at least part a beam field. The beam field may correspond to a plane defining a maximum extent that the particle beam can move relative to the target.

The particle beam may be produced by a particle accelerator configured to output a particle beam that is based on a current through superconducting windings contained within the particle accelerator. Controlling the energy of the particle beam may include setting the current to one of multiple values. Each of the multiple values may correspond to a different energy at which the particle beam is output from the particle accelerator. While the particle beam is directed along the path, the particle beam may deliver a dose of radiation to the target that exceeds twenty (20) Gray-per-second for a duration of less than five seconds. While the particle beam is directed along the path, the particle beam may deliver a dose of radiation to the target that is between twenty (20) Gray-per-second and one hundred (100) Gray-per-second for a duration of less than five seconds. While the particle beam is directed along the path, the particle beam may deliver a dose of radiation to the target that is between forth (40) Gray-per-second and one hundred and twenty (120) Gray-per-second. The 40 to 120 Gray-per-second dose may be for less than five seconds. While the particle beam is directed along the path, the particle beam may deliver a dose of radiation to the target that that exceed one or more of the following doses for a duration of less than 500 ms, for a duration that is between 10 ms and 5 s, or for a duration that is less than 5 s: 100 Gray-per-second, 200 Gray-per-second, 300 Gray-per-second, 400 Gray-per-second, or 500 Gray-per-second. The particle beam may be a Gaussian pencil beam having a size of at least two (2) millimeters sigma. The particle beam may be a Gaussian pencil beam having a size between two (2) millimeters sigma and twenty (20) millimeters sigma.

The path may be a first path and the method may include directing the particle beam along a second path at least part-way through the target that is different from the first path. The method may include controlling the energy of the particle beam while the particle beam is directed along the second path so that the particle beam treats portions of the target that are located along the second path. For example, the first and second paths may be columns that extend through the target all the way or part of the way. While the particle beam is directed along the second path, the particle beam may deliver a dose of radiation to the target that exceeds one (1) Gray-per-second for a duration of less than five hundred (500) milliseconds. The particle beam may never again be directed along the first path during treatment of the target in some examples.

The method may include blocking at least part of the particle beam using a collimator that is configurable to block a first part of the particle beam while allowing a second part of the particle beam to reach the target. The collimator may include structures comprised of material that blocks passage of the particle beam. The structures may define an edge that moves into the path of the particle beam such that the first part of the particle beam on a first side of the edge is blocked by the structures and such that the second part of the particle beam on a second side of the edge is not blocked by the structures. The collimator may include linear motors that are controlled to configure the structures to define the edge. Each of the linear motors may include a movable component and a stationary component. The stationary component may include a magnetic field generator to generate a first magnetic field. The movable component may include one or more coils to conduct current to produce a second magnetic field that interacts with the first magnetic field to cause the moveable component to move relative to the stationary component. The movable component of each linear motor may be connected to, or may be part of, a corresponding one of the structures such that the corresponding structure moves along with movement with the movable component.

An example method of treating a target using a particle beam includes directing the particle beam along a first path at least part-way through the target, controlling an energy of the particle beam while the particle beam is directed along the first path so that the particle beam treats a three-dimensional columnar portion of the target that is along the first path, and repeating directing the particle beam and controlling the energy for multiple different paths at least part-way through the target without directing the beam along a same path through the target more than once. While the particle beam is directed along each path through the target, the particle beam may deliver a dose of radiation to the target that exceeds one (1) Gray-per-second for a duration of less than five (5) seconds. The example method may include one or more of the following features, either alone or in combination.

Directing and controlling may be performed for each of multiple micro-volumes of the target. Controlling the energy of the particle beam may include moving one or more energy-absorbing plates into or out of a path of the particle beam between the target and a source of the particle beam. The particle beam may be produced by a particle accelerator configured to output a particle beam that is based on a current through superconducting windings contained within the particle accelerator. Controlling the energy of the particle beam may include setting the current to one of multiple values. Each of the multiple values may correspond to a different energy at which the particle beam is output from the particle accelerator.

An example particle therapy system includes a particle accelerator to produce a particle beam, a scanning magnet to direct the particle beam along a path at least part-way through the target, and a control system to control the scanning magnet to direct the particle beam along multiple paths at least part-way through the target and to control the energy of the particle beam so that, along each of the multiple paths, the particle beam treats a three-dimensional columnar portion of the target. While the particle beam is directed along each of the multiple paths, the particle beam delivers a dose of radiation to the target that exceeds one (1) Gray-per-second for a duration of less than five (5) seconds. The example system may include one or more of the following features, either alone or in combination.

The control system may be configured to control the scanning magnet so that the particle beam is directed along each path through the target only once. The system may include energy-absorbing structures, each of which may be configured to reduce an energy of the particle beam as the particle beam passes through the energy-absorbing structure to the target. The control system may be configured to control the energy of the particle beam by moving one or more of the energy-absorbing structures into or out of the path of the particle beam between the target and a source of the particle beam. The energy-absorbing structures may include energy-absorbing plates. The control system may be configured to treat a micro-volume of the target by controlling the scanning magnet to direct the particle beam along multiple paths at least part-way through the target and to control the energy of the particle beam so that, along each of the multiple paths, the particle beam treats a three-dimensional columnar portion of the target.

For a path among the multiple paths along which the particle beam is directed, the control system may be configured to move the one or more energy-absorbing structures into or out of the path of the particle beam while the particle beam is at the path. For a path among the multiple paths, the control system may be configured to move multiple energy-absorbing structures sequentially into the path of the particle beam. For a path among the multiple paths, the control system may be configured to move multiple energy-absorbing structures sequentially out of the path of the particle beam. An energy-absorbing plate among the energy absorbing structures may include a linear motor that is controllable to move the energy-absorbing plate into or out of the path of the particle beam. For a path among the multiple paths, the control system may be configured to move each of the one or more energy-absorbing structures into or out of the path of the particle beam in a duration of one hundred (100) milliseconds or less. For a path among the multiple paths, the control system may be configured to move each of the one or more energy-absorbing structures into or out of the path of the particle beam in a duration of fifty (50) milliseconds or less. For a path among the multiple paths, the control system may be configured to move the one or more energy absorbing structures by performing operations that include controlling a first plate among the one or more energy-absorbing structures to move during passage of the particle beam through the one or more energy-absorbing structures to the target.

The particle accelerator may include superconducting windings. The particle accelerator may be configured to produce the particle beam based on a current through the superconducting windings. The control system may be configured to control the energy of the particle beam by setting the current to one of multiple values. Each of the multiple values may correspond to a different energy at which the particle beam is output from the particle accelerator. The control system may be configured to control the particle beam to deliver, on each path, a dose of radiation to the target that exceeds twenty (20) Gray-per-second for a duration of less than five (5) seconds. The control system may be configured to control the particle beam to deliver, on each path, a dose of radiation to the target that is between twenty (20) Gray-per-second and one hundred (100) Gray-per-second for a duration of less than five (5) seconds. The control system may be configured to control the particle beam to deliver, on each path, a dose of radiation to the target that is between forty (40) Gray-per-second and one hundred and twenty (120) Gray-per-second for a specified duration.

The particle beam may be a Gaussian pencil beam having a size of at least two (2) millimeters sigma. The particle beam may be a Gaussian pencil beam having a size between two (2) millimeters sigma and twenty (20) millimeters sigma.

The particle therapy system may include a collimator that is configurable to block a first part of the particle beam while allowing a second part of the particle beam to reach the target. The collimator may include structures comprised of material to block passage of the particle beam. The structures may include an edge that moves into the path of the particle beam such that the first part of the particle beam on a first side of the edge is blocked by the structures and such that the second part of the particle beam on a second side of the edge is not blocked by the structures. The collimator may include linear motors that are controllable to configure the structures to define the edge. Each of the linear motors may include a movable component and a stationary component. The stationary component may include a magnetic field generator to generate a first magnetic field. The movable component may include one or more coils to conduct current to produce a second magnetic field that interacts with the first magnetic field to cause the moveable component to move relative to the stationary component. The movable component of each linear motor may be connected to, or may be part of, a corresponding one of the structures such that the corresponding structure moves along with movement with the movable component.

The control system may be configured to control an intensity of the particle beam along each of the multiple paths. The intensity of the particle beam may be different along at least two of the multiple paths.

The particle therapy system may include a ridge filter to spread-out a Bragg peak of the particle beam. The particle therapy system may include a range modulator wheel to spread-out a Bragg peak of the particle beam. The range modulator wheel may be configured to move in at least two dimensions to track movement of the particle beam. The control system may be configured to control an intensity of the particle beam as the particle beam impacts the range modulator wheel.

In an example, one or more non-transitory machine-readable storage media store instructions that are executable to implement an example treatment planning system for a particle therapy system. The treatment planning system includes a prediction model that characterizes the particle therapy system and a patient to be treated by the particle therapy system. The prediction model characterizes the particle therapy system at least in part by characterizing a timing at which the particle therapy system can deliver radiation. The treatment planning system also includes a relative biological effectiveness (RBE) model that characterizes a relative biological effectiveness of the radiation on tissue based on the timing of delivery of the radiation and a dose calculation engine to determine a dose regimen for delivery of the radiation to voxels of the patient. The dose calculation engine is configured to determine the dose regimen based on the prediction model and the RBE model. The treatment planning system may include one or more of the following features, either alone or in combination.

The dose regimen may specify doses and dose rates at which the radiation is to be delivered to the voxels. The treatment planning may include a sequencer to generate instructions for sequencing delivery of doses in order to optimize effective doses determined by the dose calculation engine.

The prediction model may characterize the particle therapy system based on a structure of pulses of a particle beam produced by a particle accelerator. The prediction model may characterize the particle therapy system based on a maximum dose per pulse of a particle beam produced by a particle accelerator. The prediction model may characterize the particle therapy system based on a sweep time of a scanning magnet to move a particle beam produced by a particle accelerator. The prediction model may characterize the particle therapy system based on a time it takes to change an energy of a particle beam produced by a particle accelerator. The prediction model may characterize the particle therapy system based on a time it takes to move one or more energy-absorbing structures to change an energy of a particle beam produced by a particle accelerator. The prediction model may characterize the particle therapy system based on a strategy for regulating doses of radiation. The prediction model may characterize the particle therapy system based on a time it takes to move a collimator for collimating a particle beam produced by a particle accelerator. The prediction model may characterize the particle therapy system based on a time it takes to configure a collimator for collimating a particle beam produced by a particle accelerator. The prediction model may characterize the particle therapy system based on a time it takes to control a range modulator to change a Bragg peak of particles in a particle beam produced by a particle accelerator.

The dose calculation engine may be configured to determine times at which doses specified in the dose regimen are to be delivered to the voxels of the patient based on the RBE model. The dose calculation engine may be configured to determine whether a voxel among the voxels contains targeted tissue, non-targeted tissue, or both targeted tissue and non-targeted tissue, and to determine a dose rate of radiation to the voxel based at least in part on whether the voxel contains targeted tissue, non-targeted tissue, or both targeted tissue and non-targeted tissue. The targeted tissue may include diseased tissue and the non-targeted tissue may include healthy tissue. In a case that the voxel contains non-targeted tissue only, determining the dose rate of radiation to the voxel may include determining to deliver no dose to the voxel. In a case that the voxel contains targeted tissue or both targeted tissue and non-targeted tissue, determining the dose rate of radiation to the voxel may include to deliver ultra-high dose rate radiation to the voxel.

The ultra-high dose rate radiation may include a dose of radiation that exceeds one (1) Gray-per-second for a duration of less than five (5) seconds. The ultra-high dose rate radiation may include a dose of radiation that exceeds one (1) Gray-per-second for a duration of less than 500 ms. The ultra-high dose rate radiation may include a dose of radiation that is between 40 Gray-per-second and 120 Gray-per-second for a duration of less than 500 ms.

The dose regimen may specify doses and dose rates at which the radiation is to be delivered to the voxels. The doses may include equivalent doses determined based on a weighting factor from the RBE model. The weighting factor may cause the dose to increase for a duration.

The sequencer is configured to sequence delivery of the doses based on one or more of the following, based on two or more of the following, based on three or more of the following, based on four or more of the following, based on five or more of the following, or based on all of the following: a structure of pulses of a particle beam produced by a particle accelerator, a maximum dose per pulse of the particle beam, a sweep time of a scanning magnet to move the particle beam, a time it takes to change an energy of the particle beam, a time it takes to move one or more energy-absorbing structures to change the energy of the particle beam, a strategy for regulating the doses, a time it takes to move a collimator for collimating the particle beam, a time it takes to configure the collimator, or a time it takes to control a range modulator to change a Bragg peak of particles in the particle beam.

For a voxel among the voxels, the sequencer may be configured to sequence delivery of a set of the doses in columns that pass at least part-way through the voxel. A voxel may be a micro-volume of an irradiation target to be treated using columns of radiation, may be part of such a micro-volume, or may include multiple such micro-volumes. Each dose in the set may be delivered at an ultra-high dose rate. For a column among the columns, an energy of a particle beam produced by the particle accelerator may be changed while the particle beam is stationary. The sequence of delivery may be such that, following treatment of the column, the particle beam is never again directed to treat the column.

In an example, one or more non-transitory machine-readable storage media store instructions that are executable to implement an example treatment planning system for a particle therapy system. The treatment planning system includes a prediction model that characterizes the particle therapy system and a patient to be treated by the particle therapy system and a dose calculation engine to determine a dose regimen for delivery of radiation to voxels of a patient. The dose calculation engine may be configured to determine the dose regimen based on the prediction model. The treatment planning system may include one or more of the forgoing features, either alone or in combination. The treatment planning system may include one or more of the following features, either alone or in combination.

The dose regimen may specify doses and dose rates at which the radiation is to be delivered to the voxels. The treatment planning system may include a sequencer to generate instructions for sequencing delivery of doses at rates determined by the dose calculation engine.

An example method includes storing, in computer memory, first information that characterizes a particle therapy system and a patient to be treated by the particle therapy system. The method includes storing, in computer memory, second information that characterizes a relative biological effectiveness of radiation on tissue. The method also includes determining, by one or more processing devices, a dose regimen for delivery of the radiation to voxels of the patient. The dose regimen may be determined based on the first information and the second information. The method may include one or more of the following features, either alone or in combination.

The dose regimen may specify doses and dose rates at which the radiation is to be delivered to the voxels. The method may include generating instructions for sequencing delivery of doses at rates specified in the dose regimen.

The first information may characterize the particle therapy system based on a structure of pulses of a particle beam produced by a particle accelerator. The first information may characterize the particle therapy system based on a maximum dose per pulse of a particle beam produced by a particle accelerator. The first information may characterize the particle therapy system based on a sweep time of a scanning magnet to move a particle beam produced by a particle accelerator. The first information may characterize the particle therapy system based on a time it takes to change an energy of a particle beam produced by a particle accelerator. The first information may characterize the particle therapy system based on a time it takes to move one or more energy-absorbing structures to change an energy of a particle beam produced by a particle accelerator. The first information may characterize the particle therapy system based on a strategy for regulating the doses. The first information may characterize the particle therapy system based on a time it takes to move a collimator for collimating a particle beam produced by a particle accelerator. The first information may characterize the particle therapy system based on a time it takes to configure a collimator for collimating a particle beam produced by a particle accelerator. The first information may characterize the particle therapy system based on a time it takes to control a range modulator to change a Bragg peak of particles in a particle beam produced by a particle accelerator.

Determining the dose regimen may include determining times at which doses specified in the dose regimen are to be delivered to the voxels of the patient based on the second information. Determining the dose regimen may include determining whether a voxel among the voxels contains targeted tissue, non-targeted tissue, or both targeted tissue and non-targeted tissue, and determining a dose rate of radiation to the voxel based at least in part on whether the voxel contains targeted tissue, non-targeted tissue, or both targeted tissue and non-targeted tissue. The targeted tissue may include diseased tissue and the non-targeted tissue may include healthy tissue. In a case that the voxel contains non-targeted tissue only, determining the dose rate of radiation to the voxel may include determining to deliver no dose to the voxel. In a case that the voxel contains targeted tissue or both targeted tissue and non-targeted tissue, determining the dose rate of radiation to the voxel may include determining to deliver ultra-high dose rate radiation to the voxel.

The ultra-high dose rate radiation may include a dose of radiation that exceeds one (1) Gray-per-second for a duration of less than five (5) seconds. The ultra-high dose rate radiation may include a dose of radiation that exceeds one (1) Gray-per-second for a duration of less than 500 ms. The ultra-high dose rate radiation may include a dose of radiation that is between 40 Gray-per-second and 120 Gray-per-second for a duration of less than 500 ms.

The dose regimen may specify doses and dose rates at which the radiation is to be delivered to the voxels. The doses may include equivalent doses determined based on a weighting factor from the second information. The weighting factor may cause the dose to increase for a duration.

Sequencing delivery of doses is based on one or more of the following, two or more of the following, three or more of the following, four or more of the following, five or more of the following, or all of the following: a structure of pulses of a particle beam produced by a particle accelerator, a maximum dose per pulse of the particle beam, a sweep time of a scanning magnet to move the particle beam, a time it takes to change an energy of the particle beam, a time it takes to move one or more energy-absorbing structures to change the energy of the particle beam, a strategy for regulating the doses, a time it takes to move a collimator for collimating the particle beam, a time it takes to configure the collimator, or a time it takes to control a range modulator to change a Bragg peak of particles in the particle beam.

For a voxel among the voxels, sequencing delivery of doses may include sequencing delivery of a set of the doses in columns that pass at least part-way through the voxel. Each dose in the set may be delivered at an ultra-high dose rate. For a column among the columns, an energy of a particle beam produced by a particle accelerator may be changed while the particle beam is stationary. The sequence of delivery may be such that, following treatment of the column, the particle beam is never again directed to treat the column.

An example method includes storing, in computer memory, first information that characterizes a particle therapy system and a patient to be treated by the particle therapy system; and determining, by one or more processing devices, a dose regimen for delivery of radiation to voxels of a patient. The dose regimen may be determined based on the first information. The method may include one or more of the following features, either alone or in combination.

The dose regimen may specify doses and dose rates at which the radiation is to be delivered to the voxels. The method may include generating instructions for sequencing delivery of doses at rates specified in the dose regimen.

An example system includes a particle accelerator to produce radiation for delivery to a patient; a scanning system to control the delivery of the radiation to the patient; a treatment planning system to generate a treatment plan that specifies how to deliver the radiation to voxels of the patient; and a control system to control the particle accelerator and the scanning system to deliver the radiation to the voxels of the patient in accordance with the treatment plan.

The treatment planning system may be programmed to generate the treatment plan by performing the following operations: storing, in computer memory, first information that characterizes a particle therapy system and a patient to be treated by the particle therapy system; storing, in computer memory, second information that characterizes a relative biological effectiveness of radiation on tissue; and determining, by one or more processing devices, a dose regimen for delivery of the radiation to voxels of the patient, where the dose regimen is determined based on the first information and the second information.

The treatment planning system may be programmed to generate the treatment plan by performing the following operations: storing, in computer memory, first information that characterizes a particle therapy system and a patient to be treated by the particle therapy system; and determining, by one or more processing devices, a dose regimen for delivery of radiation to voxels of a patient, where the dose regimen is determined based on the first information.

The treatment planning system may include a prediction model that characterizes the particle therapy system and a patient to be treated by the particle therapy system. The prediction model characterizes the particle therapy system at least in part by characterizing a timing at which the particle therapy system can deliver radiation. The treatment planning system also includes a relative biological effectiveness (RBE) model that characterizes a relative biological effectiveness of the radiation on tissue based on the timing of delivery of the radiation and a dose calculation engine to determine a dose regimen for delivery of the radiation to voxels of the patient. The dose calculation engine is configured to determine the dose regimen based on the prediction model and the RBE model.

The treatment planning may also include a sequencer to generate instructions for sequencing delivery of doses in order to optimize effective doses determined by the dose calculation engine.

The treatment planning system may include a prediction model that characterizes the particle therapy system and a patient to be treated by the particle therapy system, and a dose calculation engine to determine a dose regimen for delivery of radiation to voxels of a patient. The dose calculation engine may be configured to determine the dose regimen based on the prediction model.

The treatment planning may also include a sequencer to generate instructions for sequencing delivery of doses in order to optimize effective doses determined by the dose calculation engine.

The treatment planning system may include a first computing system, the control system may include a second computing system, and the first computing system may be different from the second computing system. The treatment planning system and the control system may be implemented on a same computing system. The example system may include any of the features described herein including, but not limited to, those set forth in this summary section above.

Two or more of the features described in this disclosure, including those described in this summary section, may be combined to form implementations not specifically described herein.

Control of the various systems described herein, or portions thereof, may be implemented via a computer program product that includes instructions that are stored on one or more non-transitory machine-readable storage media and that are executable on one or more processing devices (e.g., microprocessor(s), application-specific integrated circuit(s), programmed logic such as field programmable gate array(s), or the like). The systems described herein, or portions thereof, may be implemented as an apparatus, method, or electronic system that may include one or more processing devices and computer memory to store executable instructions to implement control of the stated functions.

The details of one or more implementations are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an example irradiation target treated by scanning a particle beam across entire layers sequentially.

FIG. 2 is a perspective view of an example irradiation target treated by scanning a particle beam column-by-column across the target.

FIG. 3 is a cut-away view of part of an example particle accelerator that is usable in the particle therapy system described herein.

FIG. 4 is a side view of components of an example scanning system that is usable in the particle therapy system described herein.

FIG. 5 is a perspective view of components of the example scanning system that is usable in the particle therapy system described herein.

FIG. 6 is a front view of an example magnet for use in a scanning system of the type shown in FIGS. 4 and 5 .

FIG. 7 is a perspective view of an example magnet for use in a scanning system of the type shown in FIGS. 4 and 5 .

FIG. 8 is a perspective view of an example energy degrader (range modulator) for use in a scanning system of the type shown in FIGS. 4 and 5 .

FIG. 9 is a perspective view of a process for moving a plate of the energy degrader into and out of the path of a particle beam.

FIG. 10 is a block diagram of example linear motors and example plates of an energy degrader controlled thereby.

FIG. 11 is a flowchart showing an example process for treating an irradiation target by scanning a particle beam column-by-column across the target.

FIGS. 12, 13, 14, and 15 are perspective block diagrams illustrating treatment of a column of an irradiation target by moving energy-absorbing plates sequentially into a path of a stationary particle beam.

FIGS. 16, 17, 18, and 19 are perspective block diagrams illustrating treatment of a column of an irradiation target by moving energy-absorbing plates sequentially out of a path of a stationary particle beam.

FIG. 20 is a perspective view of an example configurable collimator leaf that is usable with the example configurable collimators described herein.

FIG. 21 is a top view of configurable collimator leaves positioned relative to a treatment area of an irradiation target.

FIG. 22 is a perspective view of an example configurable collimator.

FIG. 23 is a front view of the example configurable collimator.

FIG. 24 is a perspective, view of the example configurable collimator having components portrayed in see-through to show the interiors thereof.

FIG. 25 is a perspective view of the example configurable collimator positioned relative to a patient during particle therapy treatment.

FIGS. 26 and 27 are front and perspective views, respectively, of an example particle therapy system.

FIG. 28 is a perspective view of an example particle therapy system.

FIG. 29 is a graph showing changes in particle beam spot size for different particle beam energies for different materials used in the energy degrader to change the energy of the particle beam.

FIG. 30 is a block diagram showing components of an example treatment planning system.

FIG. 31 is a cross-sectional view of voxels in a patient.

FIG. 32 is a diagram showing an example spread-out Bragg peak (SOBP) and a column that is part of example irradiation target.

FIGS. 33 to 42 are perspective block diagrams illustrating example processes for treating columns of an irradiation target by micro-volume.

FIGS. 43A and 43B are plots showing results of Monte Carlo simulations that calculate radiation dose delivered to a treatment volume and the time it takes for each voxel in that dose calculation to reach a final dose. Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

Described herein are example implementations of a treatment planning system for a particle therapy system. An example treatment plan specifies a dose regimen for treating a patient using radiation. The dose regimen may include doses to be delivered, rates at which doses are to be delivered called “dose rates”, or both doses to be delivered and dose rates. A dose in a dose regimen may include simply an amount of radiation deposited during treatment. A dose in a dose regimen may include a biological equivalent dose, also called “equivalent dose”. A biological equivalent dose may include an amount of radiation output that is needed to treat diseased tissue in the patient accounting for biological effects of tissue in the patient on the radiation deposited. In some implementations, the treatment planning system may be used to generate instructions to apply dose rates of radiation to three-dimensional treatment volumes within a patient called voxels. All or part of the treatment planning system may be implemented by executing, on one or more processing devices, one or more computer programs that are stored on, and retrieved from, one or more non-transitory machine-readable storage media.

The example treatment planning system and its variations described herein may be used to generate instructions to apply ultra-high dose rates of radiation—so called, “FLASH” dose rates of radiation—to an irradiation target. In this regard, experimental results in radiation therapy have shown an improvement in the condition of healthy tissue subjected to radiation when the treatment dose is delivered at ultra-high (FLASH) dose rates. In an example, when delivering doses of radiation at 10 to 20 Gray (Gy) in pulses of less than 500 milliseconds (ms) reaching effective dose rates of 20 to 100 Gray-per-second (Gy/S), healthy tissue experiences less damage than when irradiated with the same dose over a longer time scale, while tumors are treated with similar effectiveness. A theory that may explain this “FLASH effect” is based on the fact that radiation damage to tissue is proportionate to oxygen supply in the tissue. In healthy tissue, the ultra-high dose rate radicalizes the oxygen only once, as opposed to dose applications that radicalize the oxygen multiple times over a longer timescale. This may lead to less damage in the healthy tissue using the ultra-high dose rate.

In an example, the treatment planning system includes a predictive, accelerator-dependent timing model called the “prediction model”, a time-dependent relative biological effectiveness (RBE) model, a dose calculation engine that incorporates time-dependent RBE effects that may occur by delivering the radiation at ultra-high dose (FLASH) rates for example, and a sequencer or optimizer that sequences particle beam delivery to generate optimized ultra-high dose rate (or other) dose regimens. In this example, the treatment planning system is implemented at least in part using software and is configured—for example, written or programmed—to determine, for a proposed beam delivery, the times at which any dose is delivered to any given volume in an irradiation target.

The prediction model characterizes or models components of the particle therapy system that delivers radiation to a patient. For example, the prediction model may characterize components of a particle therapy system including the system's ability to deliver a sequence of spots or columns of radiation in a time required to provide an ultra-high dose of radiation. The prediction model may also characterize or model the patient and the treatment target, such as a tumor in the patient. The prediction model may be implemented using one or more computer programming objects; a data structure such as one or more look-up tables (LUTs), arrays, lists, or binary trees; or any appropriate software model.

The RBE model characterizes the relative biological effectiveness of radiation on tissue in a time-dependent manner. In other words, the RBE model characterizes a relative biological effectiveness of radiation on tissue based on a timing of radiation delivery to that tissue. For example, when radiation is applied at ultra-high (FLASH) dose rates, healthy tissue may experience less damage than when that same tissue is irradiated with the same dose over a longer time scale, while tumors are treated with similar effectiveness. In other words, for tumors or other diseased tissue, a critical factor for treatment is total radiation dose as opposed to dose rate, whereas for healthy tissue, dose rate is a factor in reducing damage where no damage is desired. The RBE model may include information about different types of healthy and diseased tissues and the effects different dose rates of radiation have on those different types of tissues. The RBE model may include information about how different types of healthy and diseased tissues affect the delivery and absorption of the radiation. The RBE model may also include the effects that different types or radiation have on different types of tissues at different dose rates. The RBE model may be implemented using one or more computer programming objects; a data structure such as one or more look-up tables (LUTs), arrays, lists, or binary trees; or any appropriate software models.

The dose calculation engine determines the dose regimen for a patient. For example, the dose calculation engine may determine doses of the radiation to deliver to voxels in the patient and the rates at which those doses are to be delivered. The dose calculation engine uses information from the prediction model and the RBE model in performing its calculations. In this regard, the dose calculation engine is configured—for example, written or programmed—to determine the doses and dose rates based at least in part on the time-dependent RBE of the radiation to tissue in the patient. Thus, the dose calculation engine may identify whether that tissue in the patient is healthy or diseased, use the RBE model and the prediction model to calculate the duration over which a dose or doses of radiation is/are to be delivered to that tissue based on system constraints, and scale dose to the target tissue based on the desired type of treatment. For example, the dose calculation engine may be configured to identify a target within the patient such as a malignant neoplasm and also to identify healthy tissue in the patient. The dose calculation engine may then determine the RBE of radiation on that tissue based on the RBE model. The dose calculation engine may then determine the doses of radiation to deliver to the target and the rates at which the doses are to be delivered given the constraints of the system delivering the dose and any relevant patient information based on the prediction model. To the extent possible, the dose calculation engine avoids delivery of radiation to the healthy tissue, while maintaining appropriate dosage such as ultra-high dose rates to voxels that make up the target. To the extent that radiation impacts healthy tissue, delivering that radiation at ultra-high (FLASH) dose rates may make that impact less damaging to the healthy tissue than is the case in traditional applications at lower dose rates.

Using a combination of the prediction model, the RBE model, and the dose calculation engine, all of which take timing into account in one way or another, the treatment planning system can generate time-dependent treatment plans with appropriate dose regimens, and a user can evaluate their quality. A beam delivery sequence may be created or modified manually using a forward planning approach to produce a sequenced treatment plan that takes advantage of the FLASH effect. For example, a user may manually arrange the delivery of radiation into columns having a constant beam steering or choose beam angles or collimation that reduces the degree of overlap between different columns of radiation.

The sequencer or optimizer may be configured—for example, written or programmed—to generate instructions, such as computer-executable instructions, for sequencing delivery of the doses at rates determined by the dose calculation engine. The treatment planning system may use the sequencer or optimizer to perform sequence optimization automatically by sequencing the treatment using an inverse planning approach. In an example, the sequencer uses the sequence of beam or spot delivery as additional degrees of freedom and uses optimization techniques to determine the sequence that best achieves input criteria specified by the user while accounting for time-dependent effects.

As stated, the sequencer may employ inverse planning to determine the sequence in which the doses of radiation are to be delivered. In some implementations, inverse planning includes obtaining target dose distributions of radiation and then performing a process, such as an optimization process, to determine how to deliver that radiation to achieve the objectives of the treatment plan—for example, to destroy malignant tissue—under the time constraints required to achieve ultra-high (FLASH) dose rates. In an example, given characteristics in the prediction model and the target dosage, the sequencer may determine that radiation is to be applied to voxels of the patient in columns. The sequencer may determine the radius and length of those columns, where those columns should be located in the target, and the order in which each column of radiation is to be delivered. In an example that does not use ultra-high dose rates, the sequencer may determine that radiation is to be applied in spots to layers of the target. The sequencer may determine the size, shape, and locations of the spots, the thickness of the layers, the number of layers, the number of protons in each spot, the order in which each spot is to be applied, and the order in which the layers are to be treated.

In some implementations, the sequencer is configured to sequence delivery of the doses based on one or more of the following, two or more of the following, three or more of the following, four or more of the following, five or more of the following, or all of the following: a structure of pulses of a particle beam produced by the particle accelerator, a maximum dose per pulse of the particle beam, a sweep time of a scanning magnet to move the particle beam, a time it takes to change an energy of the particle beam, a time it takes to move one or more energy-absorbing structures to change the energy of the particle beam, a strategy for regulating the doses, a time it takes to move a collimator for collimating the particle beam, a time it takes to configure the collimator, or a time it takes to control a range modulator to change a Bragg peak of particles in the particle beam.

The treatment planning system may be used with particle therapy systems for treating an irradiation target (or simply, “target”), such as a tumor, using a particle beam such as a proton or ion beam. In this regard, some such systems treat the target cross-sectional layer by layer. For example, the energy of the particle beam may be controlled to deliver a radiation dose (or simply, “dose”) to a layer and then the particle beam may be moved across all or part of that layer. Thereafter, the energy of the particle beam may be changed to deliver dose to another layer. The particle beam may be moved across all or part of that other layer and so on until the entire target is treated. For example, FIG. 1 shows treating an entire layer 10 of a target 11 using a particle beam 12 having an energy sufficient to deliver dose to layer 10 by moving the particle beam across the layer along the directions of arrows 15. Then a different layer 16 of the target 11 is treated in the same manner using a particle beam having a different energy sufficient to deliver dose to layer 16, and so on. The treatment of each layer is typically at relatively average dose rates, such as 0.1 Gray-per-second. The particle beam often penetrates healthy tissue before reaching the target. Any one location within this healthy tissue may be visited several times over the course of treatment. The dose at such a location is received over a time scale on the order of minutes.

By contrast, particle therapy systems may treat three-dimensional columns of the target using ultra-high dose rate radiation—the FLASH doses of radiation. These systems scale the ultra-high dose rate deliveries to targets using pencil beam scanning. In some examples, pencil beam scanning includes delivering a series of small beams of particle radiation that can each have a unique direction, energy, and charge. By combining doses from these individual beams, a three-dimensional target treatment volume may be treated with radiation. Furthermore, instead of organizing the treatment into layers at constant energies, the systems organize the treatment into columns defined by the direction of a stationary beam. The direction of the beam may be toward the surface of the target.

In some implementations, all or part of a column is treated before the particle beam is directed along another path through the irradiation target. In some implementations, a path through the target is all or part-way through the target. In an example, the particle beam may be directed along a path through a target and not deviate from that path. While directed along that path, the energy of the particle beam is changed. The particle beam does not move as its energy changes and, as a result, the particle beam treats all or a part of an interior portion of the target that extends along a length of the particle beam and along a width of the beam spot. The treatment is thus depth-wise along a longitudinal direction of the beam. For example, a portion of the target treated may extend from a spot of the beam at the surface of the target down through all or part of an interior of the target. The result is that the particle beam treats a three-dimensional columnar portion of the target using an ultra-high dose rate of radiation. In some examples, ultra-high dose rates of radiation include, for example, doses of radiation that exceed 1 Gray-per-second for a duration of less than 500 milliseconds (ms), that exceed 1 Gray-per-second for a duration of between 10 ms and 5 seconds (s), or that exceed 1 Gray-per-second for a duration of less than 5 s. Other examples are provided herein.

In some implementations, after a column of the target has been treated as described in the preceding paragraph, the particle beam is directed along a new, different path through the target. For example, as shown in FIG. 2 , a column 20 of target 21 is treated by varying the energy of a particle beam 22 that proceeds along the direction of arrow 28. The particle beam is then directed along a new path 24 through target 21 where it proceeds along the direction of arrow 29. A column 25 is then treated along that new path by varying the energy of the particle beam while the particle beam is stationary. As noted, the column is located along the longitudinal extent of the beam. In some implementations, the particle beam is directed along each path through the target only once when treating columns of the target.

As a result of the foregoing protocol, healthy tissue above or below target 21 is exposed to the ultra-high dose rate of radiation once and not to multiple low doses of radiation as occurs when targets are treated layer-by-layer as in FIG. 1 . Accordingly, in some implementations the particle beam is directed along a new path and upstream tissue along that path is never visited again. In this way, each location within the target can be treated at a rate that is comparable to that of an individual pencil beam modulated with the layer switching time. The average dose rate over the entire treatment may be comparable to layer-by-layer radiation deliveries, but the localized dose rate for any one spot is at an ultra-high dose rate.

In some cases, a reduction in damage to healthy tissue may occur when radiation is delivered at ultra-high dose rates. For example, when delivering radiation doses of 10 to 20 Gray in pulses of less than 500 ms—reaching effective dose rates of 20 to 100 Gray-per-second—healthy tissue may be less damaged than when irradiated with the same dose over a longer time scale, while the delivered radiation may treat tumors with the same level of effectiveness.

In some implementations, in order to achieve ultra-high dose rates, the energy of the particle beam may be changed at a rate that exceeds changes of energy used for layer-by-layer scanning. For example, ultra-high dose rates applied to columns of a target may be achieved by switching beam energy in a duration of For example, ultra-high dose rates applied to columns of a target may be achieved by switching beam energy in a duration of 10 ms or less. This may be achieved, for example, by controlling motion of the particle beam and motion of energy-absorbing plates or other structures into and out of the path of the particle beam. By way of example, a 5 centimeter (cm) deep column, which might require 5 layer switches, may require 250 ms of down-time during which particle beam is not delivered, allowing 250 ms of beam delivery during which 10 to 20 Gray of dose may be delivered. Faster motion of the energy-absorbing plates and/or additional coordination of beam motion may further decrease the layer switching time allowing even more time to deliver the required treatment dose while still meeting the requirement for a localized ultra-high dose rate.

Described below are example implementations of a particle therapy system configured to deliver radiation at ultra-high dose rates through three-dimensional columns of a target in accordance with a treatment plan determined by a treatment planning system. In an example implementation, the particle therapy system is a proton therapy system. As described herein, an example proton therapy system scans a proton beam in three dimensions across an irradiation target in order to destroy malignant tissue. FIG. 3 shows a cross-section of components 310 of an example superconducting synchrocyclotron that may be used to provide a particle (e.g., a proton) beam in the proton therapy system. In this example, components 310 include a superconducting magnet 311. The superconducting magnet includes superconducting coils 312 and 313. The superconducting coils are formed of multiple integrated conductors, each of which includes superconducting strands—for example, four strands or six strands—wound around a center strand which may itself be superconducting or non-superconducting. Each of the superconducting coils 312, 313 is for conducting a current that generates a magnetic field (B). The magnetic yokes 314, 315 or smaller magnetic pole pieces shape that magnetic field in a cavity 316 in which particles are accelerated. In an example, a cryostat (not shown) uses liquid helium (He) to conductively cool each coil to superconducting temperatures, e.g., around 4° Kelvin (K).

In some implementations, the particle accelerator includes a particle source 317, such as a Penning Ion Gauge—PIG source, to provide an ionized plasma column to cavity 316. Hydrogen gas, or a combination of hydrogen gas and a noble gas, is ionized to produce the plasma column. A voltage source provides a varying radio frequency (RF) voltage to cavity 316 to accelerate particles from the plasma column within the cavity. As noted, in an example, the particle accelerator is a synchrocyclotron. Accordingly, the RF voltage is swept across a range of frequencies to account for relativistic effects on the particles, such as increasing particle mass, when accelerating particles within the acceleration cavity. The RF voltage drives a dee plate contained within the cavity and has a frequency that is swept downward during the accelerating cycle to account for the increasing relativistic mass of the protons and the decreasing magnetic field. A dummy dee plate acts as a ground reference for the dee plate. The magnetic field produced by running current through the superconducting coils, together with sweeping RF voltage, causes particles from the plasma column to accelerate orbitally within the cavity and to increase in energy as a number of turns increases.

The magnetic field in the cavity is shaped to cause particles to move orbitally within the cavity. The example synchrocyclotron employs a magnetic field that is uniform in rotation angle and falls off in strength with increasing radius. In some implementations, the maximum magnetic field produced by the superconducting (main) coils may be within the range of 4 Tesla (T) to 20 T at a center of the cavity, which falls off with increasing radius. For example, the superconducting coils may be used in generating magnetic fields at, or that exceed, one or more of the following magnitudes: 4.0 T, 4.1 T, 4.2 T, 4.3 T, 4.4 T, 4.5 T, 4.6 T, 4.7 T, 4.8 T, 4.9 T, 5.0 T, 5.1 T, 5.2 T, 5.3 T, 5.4 T, 5.5 T, 5.6 T, 5.7 T, 5.8 T, 5.9 T, 6.0 T, 6.1 T, 6.2 T, 6.3 T, 6.4 T, 6.5 T, 6.6 T, 6.7 T, 6.8 T, 6.9 T, 7.0 T, 7.1 T, 7.2 T, 7.3 T, 7.4 T, 7.5 T, 7.6 T, 7.7 T, 7.8 T, 7.9 T, 8.0 T, 8.1 T, 8.2 T, 8.3 T, 8.4 T, 8.5 T, 8.6 T, 8.7 T, 8.8 T, 8.9 T, 9.0 T, 9.1 T, 9.2 T, 9.3 T, 9.4 T, 9.5 T, 9.6 T, 9.7 T, 9.8 T, 9.9 T, 10.0 T, 10.1 T, 10.2 T, 10.4 T, 10.5 T, 10.6 T, 10.7 T, 10.8 T, 10.9 T, 11.0 T, 11.1 T, 11.2 T, 11.3 T, 11.4 T, 11.5 T, 11.6 T, 11.7 T, 11.8 T, 11.9 T, 12.0 T, 12.1 T, 12.2 T, 12.3 T, 12.4 T, 12.5 T, 12.6 T, 12.7 T, 12.8 T, 12.9 T, 13.0 T, 13.1 T, 13.2 T, 13.3 T, 13.4 T, 13.5 T, 13.6 T, 13.7 T, 13.8 T, 13.9 T, 14.0 T, 14.1 T, 14.2 T, 14.3 T, 14.4 T, 14.5 T, 14.6 T, 14.7 T, 14.8 T, 14.9 T, 15.0 T, 15.2 T, 15.3 T, 15.4 T, 15.5 T, 15.6 T, 15.7 T, 15.8 T, 15.9 T, 16.0 T, 16.1 T, 16.2 T, 16.3 T, 16.4 T, 16.5 T, 16.6 T, 16.7 T, 16.8 T, 16.9 T, 17.0 T, 17.1 T, 17.2 T, 17.3 T, 17.4 T, 17.5 T, 17.6 T, 17.7 T, 17.8 T, 17.9 T, 18.0 T, 18.1 T, 18.2 T, 18.3 T, 18.4 T, 18.5 T, 18.6 T, 18.7 T, 18.8 T, 18.9 T, 19.0 T, 19.1 T, 19.2 T, 19.3 T, 19.4 T, 19.5 T, 19.6 T, 19.7 T, 19.8 T, 19.9 T, 20.0 T, 20.1 T, 20.2 T, 20.3 T, 20.4 T, 20.5 T, 20.6 T, 20.7 T, 20.8 T, 20.9 T, or more. Furthermore, the superconducting coils may be used in generating magnetic fields that are outside the range of 4 T to 20 T or that are within the range of 4 T to but that are not specifically listed herein.

In some implementations, such as the implementations shown in FIG. 3 , the relatively large ferromagnetic magnetic yokes 314, 315 act as returns for stray magnetic fields produced by the superconducting coils. In some systems, a magnetic shield (not shown) surrounds the yokes. The return yokes and the shield together act to reduce stray magnetic fields, thereby reducing the possibility that stray magnetic fields will adversely affect the operation of the particle accelerator.

In some implementations, the return yokes and shield may be replaced by, or augmented by, an active return system. An example active return system includes one or more active return coils that conduct current in a direction opposite to current through the main superconducting coils. In some example implementations, there is an active return coil for each superconducting main coil, e.g., two active return coils—one for each main superconducting coil. Each active return coil may also be a superconducting coil that surrounds the outside of a corresponding main superconducting coil concentrically.

By using an active return system, the relatively large ferromagnetic magnetic yokes 314, 315 can be replaced with magnetic pole pieces that are smaller and lighter. Accordingly, the size and weight of the synchrocyclotron can be reduced further without sacrificing performance. An example of an active return system that may be used is described in U.S. Pat. No. 8,791,656 entitled “Active Return System”, the contents of which are incorporated herein by reference.

At or near the output of an extraction channel of the particle accelerator, there may be one or more beam shaping elements including a scanning system. Components of the scanning system may be mounted on, or otherwise attached to, a nozzle for positioning relatively close to the patient during treatment.

Referring to FIG. 4 , in an example implementation, at the output of extraction channel 420 of synchrocyclotron 421 (which may have the configuration of FIG. 3 ) are example scanning components 422 that may be used to move the particle beam three-dimensionally over and through an irradiation target. FIG. 5 also shows examples of the components of FIG. 4 . These include, but are not limited to, one or more scanning magnets 424, an ion chamber 425, an energy degrader 426, and a configurable collimator 428. Some implementations may not include a configurable collimator. In example implementations such as these, the particle beam passes through the energy degrader and to the patient without subsequent conditioning such as collimation. Other components that may be down-beam of the extraction channel are not shown in FIG. 4 or 5 and may include, for example, one or more scattering devices for changing beam spot size. An example scattering device includes a plate or range modulator that disperses the particle beam as the particle beam passes through the scattering device.

In an example operation, scanning magnet 424 is controllable in two dimensions (e.g., Cartesian XY dimensions) to position the particle beam in those two dimensions and to move the particle beam across at least a part of an irradiation target. Ion chamber 425 detects the dosage of the beam and feeds-back that information to a control system to adjust beam movement. Energy degrader 426 is controllable to move structures into, and out of, the path of the particle beam to change the energy of the particle beam and therefore the depth to which dose of the particle beam will be deposited in the irradiation target. Examples of such structures include, but are not limited to, energy-absorbing plates; polyhedra such as wedges, tetrahedra, or toroidal polyhedra; and curved three-dimensional shapes, such as cylinders, spheres, or cones. In this way, the energy degrader can cause the particle beam to deposit doses of radiation in the interior of an irradiation target to treat columns of the target. In this regard, when protons move through tissue, the protons ionize atoms of the tissue and deposit a dose along their path. The Bragg peak is a pronounced peak on the Bragg curve which plots the energy loss of ionizing radiation during its travel through tissue. The Bragg peak represents the depth at which most protons deposit within tissue. For protons, the Bragg peak occurs right before the particles come to rest. Accordingly, the energy of the particle beam may be changed to change the location of its Bragg peak and, therefore, where a majority of the dose of protons will deposit in depth in the tissue.

FIGS. 6 and 7 show views of an example scanning magnet 424. In this example, scanning magnet 424 includes two coils 441, which control particle beam movement in the X dimension, and two coils 442, which control particle beam movement in the Y dimension. Control is achieved, in some implementations, by varying current through one or both sets of coils to thereby vary the magnetic field(s) produced thereby. By varying the magnetic field(s) appropriately, the particle beam can be moved in the X and/or Y dimension across the irradiation target. The energy degrader described previously can move the beam in the Z dimension through the target, thereby enabling scanning in three dimensions.

Referring back to FIG. 4 , a current sensor 427 may be connected to, or be otherwise associated with, scanning magnet 424. For example, the current sensor may be in communication with, but not connected to, the scanning magnet. In some implementations, the current sensor samples current applied to magnet 424, which may include current to the coil(s) for controlling beam scanning in the X dimension and/or current to the coil(s) for controlling beam scanning in the Y dimension. The current sensor may sample current through the magnet at times that correspond to the occurrence of pulses in the particle beam or at a rate that exceeds the rate that the pulses occur in the particle beam. The samples, which identify the magnet current, are correlated to detection of the pulses by the ion chamber described below. For example, the times at which pulses are detected using the ion chamber may be correlated in time to samples from the current sensor, thereby identifying the current in the magnet coil(s) at the times of the pulses. Using the magnet current, it thus may be possible to determine the location within the irradiation target where each pulse, and thus dose of radiation—that is, dose of particles—was delivered. The location of the dose delivered within the target may also be determined based on the configuration of the energy degrader, for example, based on the number of plates in the beam path.

During operation, the magnitude value of the magnet current may be stored for each location at which a dose is delivered, along with the amount (e.g., intensity) of the dose. A control system, which may be either on the accelerator or remote from the accelerator and which may include memory and one or more processing devices, may correlate the magnet current to coordinates within the irradiation target, and those coordinates may be stored along with the amount of the dose. For example, the location may be identified by depth-wise layer number and Cartesian XY coordinates or by Cartesian XYZ coordinates, with the depth-wise layer corresponding to the Z coordinate. In some implementations, both the magnitude of the magnet current and the coordinate locations may be stored along with the dose at each location. This information may be stored in memory either on, or remote from, the accelerator. This information may be used to track treatment of the target and to maintain a record of that treatment.

Ion chamber 425 detects dosage, such as one or more individual doses, applied by the particle beam to positions within the irradiation target by detecting the numbers of ion pairs created within a gas caused by incident radiation. The numbers of ion pairs correspond to the dose provided by the particle beam. That information is fed-back to the control system and stored in memory along with the time that the dose is provided. This information may be correlated to, and stored in association with, the location at which the dose was provided and/or the magnitude of the magnet current at that time, as described above.

As noted previously, some implementations do not include a configurable collimator. In example implementations that include a configurable collimator, configurable collimator 428 may be located down-beam of the scanning magnets and down-beam of the energy degrader, as shown in FIGS. 4 and 5 . The configurable collimator may trim the particle beam on a spot-by-spot basis during movement of the particle beam from path to path through the target. The configurable collimator may also trim the particle beam while the particle beam is stationary on the target and when the energy of the stationary particle beam changes to impact different portions of the interior of the target. For example, the particle beam may spread along its diameter as it enters the interior of the target. That spread may change for different depths within the interior. The collimator may be configured to trim the particle beam to account for that spread. For example, the collimator may be configured and reconfigured so that the diameter or size of the spot remains the same for the entirety of a column being treated.

In some implementations, the configurable collimator may include sets of leaves that face each other and that are movable into and out of carriages to create an aperture shape. Parts of the particle beam that exceed the aperture shape are blocked, and do not pass to the patient. The parts of the beam that pass to the patient are at least partly collimated, thereby providing a beam with a relatively precise edge. In some implementations, each leaf in a set of leaves disposed, for example, on a carriage in the configurable collimator is controllable using a single linear motor to define an edge that is movable into a path of the particle beam such that a first part of the particle beam on a first side of the edge is blocked by the multiple leaves and such that a second part of the particle beam on a second side of the edge is not blocked by the multiple leaves. The leaves in each set are individually controllable during scanning to trim an area as small as a single spot, and can also be used to trim larger multi-spot areas. The ability to trim a single spot may be significant when treating a column of a target, since different amounts of trimming may need to be performed for different particle beam energies.

FIG. 8 shows an example range modulator 460, which is an example implementation of energy degrader 426. In some implementations, range modulator 460 may be located down-beam of the scanning magnets between the configurable collimator and the patient. In some implementations, such as that shown in FIG. 8 , the range modulator includes a series of plates 461. The plates may be made of one or more of the following example materials: polycarbonate such as LEXAN™, carbon, beryllium, boron carbide, a composite material comprised of boron carbide and graphite, or a material of low atomic number. Other materials, however, may be used in place of, or in addition to, these example materials. In other implementations of the energy degrader that include polyhedra such as wedges, tetrahedra, or toroidal polyhedral, or curved three-dimensional structures, such as cylinders, spheres, or cones, these structures may be made of one or more of the following example materials: polycarbonate such as LEXAN™, carbon, beryllium, boron carbide, a composite material comprised of boron carbide and graphite, or a material of low atomic number.

In some implementations, structures of the range modulator containing boron carbide may include only boron carbide; that is, the structures may be pure boron carbide. In some implementations, structures containing boron carbide may include boron carbide in combination with another material, such as graphite, polycarbonate, carbon, or beryllium. In some implementations, every structure—for example, plate, polyhedron, or curved three-dimensional structure—in the energy degrader may contain all or part boron carbide. In some implementations, different structures—for example, plates, polyhedra, or curved three-dimensional structures—in the energy degrader may include different materials. For example, one or more plates in the energy degrader may be made of pure boron carbide and one or more other plates of the same energy degrader may be made of or include one or more of polycarbonate, carbon, and/or beryllium. Other materials may also be used. For example, one or more plates or portions thereof in the energy degrader may be made of a composite material comprised of boron carbide and graphite.

One or more of the plates is movable into, or out of, the beam path to thereby change the energy of the particle beam and, thus, the depth at which most of the dosage of the particle beam is deposited within the irradiation target. Plates are moved physically into and out of the path of the particle beam. For example, as shown in FIG. 9 , a plate 470 moves along the direction of arrow 472 between positions in the path of the particle beam 473 and outside the path of the particle beam. The plates are computer-controlled. Generally, the number of plates that are moved into the path of the particle beam corresponds to the depth at which scanning of an irradiation target is to take place. Thus, dosage from the particle beam can be directed into the interior of a target by appropriate control of one or more plates.

In some implementations, individual plates of range modulator 460 are each coupled to, and driven by, a corresponding motor 464. In general, a motor includes a device that converts some form of energy into motion. A motor may be rotary or linear, and may be electric, hydraulic, or pneumatic. For example, each motor may be an electrical motor that drives a lead screw to extend a plate into the beam field or to retract a plate out of the beam field, including to cause motion of the plate to track or to trail motion of the particle beam within the beam field. For example, each motor may be a rotary motor that drives a corresponding linear actuator to control movement of a corresponding structure. In some implementations, individual plates of range modulator 460 are each coupled to, and driven by, a corresponding actuator. In some examples, actuators include mechanical or electro-mechanical devices that provide controlled movements and that can be operated electrically by motors, hydraulically, pneumatically, mechanically, or thermally. In some examples, an actuator includes any type of motor that is operated by a source of energy, such as electric current, hydraulic fluid pressure, or pneumatic pressure, and that converts that energy into motion.

In some implementations, an energy degrader containing boron carbide structures (or structures comprised of other material) may be located in the treatment room where the particle beam is applied to the patient. For example, the energy degrader may be located between the scanning magnet and the patient. In an example, the energy degrader may be located in a nozzle on a system's inner gantry, examples of which are described with respect to FIGS. 26, 27, and 28 .

The energy degrader may be located close to the patient so as to limit the amount that the particle beam is scattered or dispersed following passage through one or more plates or other structures. In some implementations, the energy degrader may be located no more than four meters from the patient along a beam line of the particle beam. In some implementations, the energy degrader may be located no more than three meters from the patient along a beamline of the particle beam. In some implementations, the energy degrader may be located no more than two meters from the patient along a beam line of the particle beam. In some implementations, the energy degrader may be located no more than one meter from the patient along a beamline of the particle beam. In some implementations, the energy degrader may be located no more than one-half a meter from the patient along a beamline of the particle beam. In some implementations, the energy degrader may be located within the nozzle no more than four meters from the patient along a beamline of the particle beam. In some implementations, the energy degrader may be located within the nozzle no more than three meters from the patient along a beamline of the particle beam. In some implementations, the energy degrader may be located within the nozzle no more than two meters from the patient along a beamline of the particle beam. In some implementations, the energy degrader may be located within the nozzle no more than one meter from the patient along a beam line of the particle beam. In some implementations, the energy degrader may be located within the nozzle no more than one-half a meter from the patient along a beam line of the particle beam.

In general, boron carbide may be cheaper and safer to use than some other materials that may be used to degrade the energy of the particle beam, such as beryllium. In general, boron carbide has a relatively low atomic weight and a high density and may compare favorably in its scattering properties to some other materials that may be used to degrade the energy of the particle beam, such as carbon (e.g., graphite) and polycarbonate. Reducing the beam scattering results in a reduced beam spot size; that is, the cross-sectional size of the beam. A reduced spot size provides for improved conformality in a pencil beam scanning system and higher localized dose rate. In other words, reducing the spot size reduces the area over which dose is deposited. As a result, the concentration of protons deposited within a single spot increases, thereby increasing the dose rate within the area of the single spot. Increasing the dose rate within the area of the single spot is desirable when performing scanning using ultra-high (or FLASH) dose rates since it facilitates deposition of an ultra-high dose of protons within a prescribed period. Examples of periods during which ultra-high doses are applied are described herein.

FIG. 29 is a graph showing the change in particle beam spot size for different particle beam energies for different materials used in the energy degrader to change the energy of the particle beam. In this example, LEXAN™, carbon (e.g., graphite), boron carbide, and beryllium are shown. According to the graph of FIG. 29 , for example, a boron carbide degrader structure produces a particle beam having a spot size of less than 1.2 centimeters (cm) sigma at an energy of 70 MeV (Million electron Volts). In this example, the spot size is measured at the output of the degrader structure. The spot may scatter the farther the beam travels through the air, which will cause an increase in spot size. However, placing the degrader sufficiently close to the patient will limit scattering. In addition, in some but not all cases, a configurable collimator may be placed between the energy degrader and the patient to collimate the particle beam.

In addition to the foregoing advantages, a boron carbide based energy degrader may be reduced in size relative to energy degraders that use polycarbonate, for example. That is, a boron carbide based energy degrader may achieve substantially the same effect as a polycarbonate based energy degrader, but the boron carbide based energy degrader may have a smaller form factor than the polycarbonate based energy degrader. This is because the density of boron carbide is greater than the densities of polycarbonate. In some examples, an energy degrader comprised of pure boron carbide plates may be 30 centimeters (cm) to thick along the beamline. The plates may have the same or varying thicknesses. The thickness of the plates and of the energy degrader itself will depend upon various factors such as the overall amount of energy change required and the number of layers to be treated, which may determine the number and thickness of each of the plates.

The reduced size of an energy degrader comprised of boron carbide makes the energy degrader less obtrusive in the treatment room. For example, an energy degrader comprised of all or some boron carbide structures may be housed within the nozzle on the inner gantry. The nozzle, including the energy degrader may be retracted fully within the inner gantry, thereby taking the energy degrader out of the way of a technician administering the treatment. In some implementations, the inner gantry may be flush with a wall of the treatment room, in which case retracting the nozzle and the energy degrader fully within the inner gantry causes the nozzle and energy degrader to retract fully within the wall.

FIG. 10 shows an example implementation of a range modulator such as a boron carbide based range modulator that uses linear motors to control operations of energy-absorbing plates 101, 102, and 103. The range modulator of FIG. 10 may otherwise have the configuration of the range modulator of FIG. 8 . Although only three plates are shown in the example of FIG. 10 , any appropriate number of plates may be included, as illustrated by ellipses 106.

Taking plate 102 as an example, an example linear motor that controls operation of plate 102 includes a movable component and stationary component comprised of two parts—in this example, magnets 110 a and 110 b. The two magnets are arranged side-by-side, with their poles aligned. That is, as shown, the positive pole (+) of magnet 110 a is aligned to the positive pole (+) of magnet 110 b, and the negative pole (−) of magnet 110 a is aligned to the negative pole (−) of magnet 110 b. The movable component includes a coil-carrying plate 109 between magnets 110 a and 110 b. Coil-carrying plate 109 is connected physically to energy-absorbing plate 102 and controls movement of energy-absorbing plate 102 along the directions of arrow 111, e.g., into and out of the path of the particle beam.

As explained, coil-carrying plate 109 includes one or more conductive traces or other conductive structures that pass current in order to generate a magnetic field. The magnetic field is controlled by controlling the current through the coil-carrying plate in order to control movement of the coil-carrying plate, and thus of energy-absorbing plate 102. That is, current through the coils generates a magnetic field that interacts with the magnetic field produced by magnets 110 a and 110 b. This interaction causes movement of coil-carrying plate 109 and of energy-absorbing plate 102 along the direction of arrow 111, either into, or out of, the particle beam path. For example, larger magnetic fields generated by the coil-carrying plate 109 may cause the energy-absorbing plate to move into the particle beam path and smaller or opposite magnetic fields generated by the coil-carrying plate may cause the energy-absorbing plate to retract away from the particle beam path.

In some implementations, the conductive traces or other conductive structures on the coil-carrying plate may include three windings embedded in aluminum. In some implementations, the energy-absorbing plate may be physically attached to the coil-carrying plate and move with the coil-carrying plate. In some implementations, the number of windings and the materials used may be different than those described herein. In some implementations, the coil-carrying plate may be an integral part of the energy-absorbing plate. For example, the energy-absorbing plate itself may include the conductive structures or traces.

As shown in FIG. 10 , in some implementations, the current through the coil-carrying plates may be controlled by signals received from a control system, such as computing system 114. The computing system may be susceptible to neutron radiation and, therefore, may be located in a remote room 116. In some implementations, remote room 116 may be shielded from neutron radiation produced by the particle accelerator. In some implementations, the remote room may be located far enough away from the treatment room 117 so as not to be affected by neutron radiation from the particle accelerator. In some implementations, the computing system may be located in the treatment room, but may be shielded from neutron radiation emitted by the particle accelerator. In some implementations, all computing functionality is shielded from neutron radiation and the electronics that are not shielded can still operate in the presence of neutron radiation. Encoders are examples of such electronics.

In this regard, encoders (not shown) may include or more of laser sensors, optic sensors, or diode sensors. The encoders detect movement of the coil-carrying plates, e.g., by detecting where markings or other indicia on the coil-carrying plates or on structures connected to, and that move with, the coil-carrying plates are located relative to the encoders. This information about where the coil-carrying plates are is fed back to the computing system and is used by the computing system to confirm the position of the coil-carrying plates during operation. The encoders may be located at any appropriate location. In some implementations, the encoders are located on a housing that includes the coil-carrying plates. As the plates move, markings or other indicia that move with the coil-carrying plates move past the encoders. The encoders then relay that information to computing system 114. Computing system 114 may use that information to control operation of the range modulator, including positioning its energy-absorbing plates.

Computing system 114, which may be comprised of one or more processing devices, may be programmed to control the proton therapy system to deliver proton therapy based on a treatment plan, including components of the scanning system to implement ultra-high dose rate radiation treatment column-by-column in an irradiation target, such as a volume in a patient containing diseased tissue. For example, the computing system may be controllable based on the treatment plan to output one or more control signals to control one or more of the linear motors to extend or to retract one or more of the energy-absorbing plates during scanning. For example, the computing system may be controllable based on the treatment plan to output one or more control signals to control one or more electrical motors to extend or to retract one or more of the energy-absorbing plates during scanning. The computing system may include one or more processing devices, such as microprocessors, microcontrollers, field-programmable gate arrays (FPGAs), or applications-specific circuits (ASICs), for example.

FIG. 30 shows components of an example treatment planning system 1200 that may be implemented on the control system, such as computing system 114, or that may be implemented on a different computing system that is separate from the control system. The treatment planning system includes modules—which may include, for example, data and/or routines comprised of source code, compiled code, or interpreted code—to implement different functions of the treatment planning system. The modules may be time-dependent in the sense that delivery of radiation at an ultra-high dose rate is dependent upon the ability to deliver that radiation at a specific dose in a specific time. Examples of doses and times are provided herein.

An example module includes a prediction model 1201. The prediction model characterizes or models the particle therapy system including, but not limited to, a particle accelerator that generates radiation for delivery to a patient and the scanning system used to direct the radiation. The prediction model also characterizes or models the patient to be treated, including volumes where radiation is to be delivered and volumes where radiation is not to be delivered. In some implementations, the prediction model may be implemented at least in part using one or more data structures stored in computer memory. An example data structure includes a collection of data values, the relationships among those values, and functions or operations that can be applied to the data. Examples of data structures that may be used to implement the prediction model may include one or more of the following: lookup tables (LUTs), arrays, stacks, queues, linked lists, trees, graphs, tries or prefix trees, or hash tables. The prediction model may also include executable code to interact with other modules and to retrieve data from a data structure. The prediction model may also be implemented using one or more computer programming objects written in an object-oriented language.

Prediction model 1201 may be populated manually, automatically, or a combination of manually and automatically. For example, to populate the prediction model manually, code to implement part of the prediction model may be executed to generate prompts that are displayed to a treatment planning technician on an electronic display device. A treatment planning technician may enter information into the prediction model in response to the prompts. The information may include values that are based on, or that are assigned to, physical properties of the particle therapy system, the patient, the target in the patient, and other relevant parameters. The information may relate to the capabilities of the particle therapy system to deliver radiation to a patient time-sequentially; for example, in a sequence of spots or columns over a time required to deliver a FLASH dose or radiation. For example, the information may relate to, but is not limited to, a structure of pulses of a particle beam produced by the particle accelerator—for example the duration of each pulse, a maximum dose per pulse of the particle beam—for example a number of particles per pulse, a sweep time of a scanning magnet to move the particle beam a specified distance, a time it takes to change an energy of the particle beam—for example by changing the energy of a variable-energy accelerator, a time it takes to move one or more energy-absorbing structures to change the energy of the particle beam, a strategy for regulating the doses—for example, to apply ultra-high dose rate radiation in columns of a target or to apply dose at lower rates layer-by-layer in a target, a time it takes to move a collimator for collimating the particle beam, a time it takes to configure the collimator, and/or a time it takes to control a range modulator to change a Bragg peak of particles in the particle beam. Thus, in general, the prediction model may characterize the timing at which radiation—for example, particle therapy—is or can be delivered to the patient. The information may include the type of disease—for example, tumor—to be treated, the location of the tumor in the patient's body specified in XYZ coordinates for example, the size and shape of the diseased tissue including its volume, the type of healthy tissue surrounding the diseased tissue, the location of the healthy tissue specified in XYZ coordinates for example, the size and shape of the healthy tissue including its volume, and any other information about the patient and the disease that may be pertinent to treatment such as past medical history, prior treatment, surgery, and the like.

In some implementations, all or some of the foregoing information in the prediction model may be stored in the control system, such as computing system 114. The treatment planning system may query the control system to obtain all or some of this information absent input from a user.

An example module includes a RBE model 1202. As explained previously, the RBE model characterizes the relative biological effectiveness of radiation on tissue in a time-dependent manner. For example, when radiation is applied at ultra-high (FLASH) dose rates, healthy tissue experiences less damage than when that same tissue is irradiated with the same dose over a longer time scale, while tumors are treated with similar effectiveness. The RBE model may include information about different types of healthy and non-healthy tissues and the effects different dose rates of radiation have on those different types of tissues. For example, the RBE model may specify the doses of radiation necessary to treat adenomas, carcinomas, sarcomas, or lymphomas effectively. The doses needed to treat such tumors are not necessarily time-dependent; accordingly dose rates may not be specified. However, in some implementations, dose rates for treating tumors may be specified in the RBE model. For reasons explained previously, the rate at which dose is applied to healthy tissue during radiation treatment can affect the damage that the radiation causes to the healthy tissue. Accordingly, the RBE model may specify time-dependent effects of dose rates on healthy tissue. In this regard, examples of non-healthy tissue include benign and malignant neoplasms and bodily tissue affected by other types of diseases. Examples of healthy tissue include bones, skin, muscle, or organs that are not affected by disease. The RBE model may also include the effects that different types or radiation have on different types of tissues at different dose rates. The example systems described herein use proton radiation; however, the RBE model may include information about other types of radiation such as other types of ion radiation, photon radiation, or X-ray radiation.

The RBE model may also include information about how different types of healthy and non-healthy tissues affect radiation applied to those tissues. As explained previously, an equivalent dose may include an amount of radiation deposited that is needed to treat diseased tissue in the patient accounting for biological effects of tissue in the patient on the radiation deposited. In this regard, some tissue may not absorb all of the dose of radiation deposited. Accordingly, the dose may be weighted using information from the RBE model to account for the biological effects of tissue on the radiation. The resulting equivalent dose takes biological effects on radiation into account. For example, given tissue may degrade the destructive effect of a certain type of radiation by 10%. Accordingly, the equivalent dose may be increased by 10% to account for this biological factor.

In some implementations, the RBE model may be implemented at least in part using one or more data structures stored in computer memory. An example data structure includes a collection of data values, the relationships among those values, and functions or operations that can be applied to the data. Examples of data structures that may be used to implement the RBE model may include one or more of the following: lookup tables (LUTs), arrays, stacks, queues, linked lists, trees, graphs, tries or prefix trees, or hash tables. The RBE model may also include executable code to interact with other modules and to retrieve data from a data structure. The RBE model may also be implemented using one or more computer programming objects written in an object-oriented language.

RBE model 1202 may be populated manually, automatically, or a combination of manually and automatically. For example, to populate the RBE model manually, code to implement part of the RBE model may be executed to generate prompts that are displayed to a treatment planning technician on an electronic display device. A treatment planning technician may enter information into the RBE model in response to the prompts. The information may include values that are based on, or that are assigned to, different types of tumors, different types of radiation, different doses, and different dose rates. For example, the RBE model may include one or more lists of disease, such as tumors. The RBE model may identify different types of radiation, such as proton, photon, or X-ray, that can treat each disease. The RBE model may identify, for each type of radiation, one or more ranges of doses that can treat a given volume of disease. The RBE model may identify, for each type of radiation, one or more ranges of dose rates that can treat a given volume of disease. In this regard, as noted, dose rate may not always be a factor in treating diseased tissue; the dose itself may be critical in some cases irrespective of dose rate. The RBE model may identify different types of healthy tissue, such as muscle, bone, skin, and organs. The RBE may specify the effect that different dose rates—for example, dose applied over a period of time—of different types of radiation have on those types of tissue. For example, the RBE may specify the effects of different levels of FLASH and non-FLASH dose rates for different types of radiation on different types of tissue. For example, the RBE may specify the effects of different levels of FLASH and non-FLASH dose rates for proton radiation on healthy muscle, bone, skin, and organs. The effects may be quantified. For example, damage to tissue may be specified on a numerical scale of 0 to 10, with 0 being no damage and 10 being destruction of the tissue. For example, the effects may be specified using descriptive information that can be read and understood electronically, for example, by the dose calculation engine. The RBE model may specify the effects of different types of radiation on that radiation's effectiveness and include weighting factors to counteract these effects.

In some implementations, all or some of the foregoing information in the RBE model may be stored in the control system, such as computing system 114. The treatment planning system may query the control system to obtain all or some of this information absent input from a user such as a treatment planning technician.

An example module includes dose calculation engine 1203. Dose calculation engine 1203 is configured—for example, written or programmed—to determine doses of radiation to deliver to voxels in the patient and, in some examples, the rates at which those doses are to be delivered to the patient. In this regard, dose calculation engine 1203 may receive, from a treatment planning technician for example, a total target radiation dose to deliver to diseased tissue in the patient, the dose distribution across the tissue, or both the total target dose and the dose distribution. The dose calculation engine obtains information about the system delivering the radiation and the patient from the prediction model. The dose calculation engine obtains information about the RBE of the radiation to be delivered by the system to the diseased tissue and the healthy tissue from the RBE model. The information from the prediction model and the RBE model is then used to determine doses and dose rates of radiation to be applied to the patient.

For example, the dose calculation engine obtains the composition of a tumor to be treated in the patient. As noted, this information may be obtained, for example, from the prediction model or from input by a treatment planning technician. The composition may include the type of the tumor, the size or volume of the tumor, and the shape of the tumor. The dose calculation engine obtains information about healthy tissue in the patient adjacent to the tumor. This information may be obtained, for example, from the prediction model or from input by a treatment planning technician. The information may include the type of healthy tissue, the location of the healthy tissue relative to the diseased tissue, and whether the healthy tissue has previously been exposed to radiation. The dose calculation engine also obtains information about the maximum dose rates that can be achieved using the particle accelerator, the scanning system, and other hardware in the particle therapy system. This information may be obtained from the prediction model or determined based on information in the model. The dose calculation engine also obtains information about how doses of the radiation applied by the system treat, effect, or both treat and effect the diseased tissue and the healthy tissue. This information may be obtained from the RBE model. The dose calculation engine also obtains information about how tissue within the patient affects radiation applied by the system (for example, radiation absorption) and any weighting factors needed to counteract such effects. This information may be obtained from the RBE model.

The dose calculation engine is configured to determine the dose regimen to be applied to the patient. The dose regimen may include equivalent doses to be delivered to the patient and the rates at which those equivalent doses are to be delivered based on the foregoing information obtained from the prediction model and the foregoing information obtained from the RBE model. For example, as explained previously, when radiation is applied at ultra-high (FLASH) dose rates, healthy tissue experiences less damage than when that same tissue is irradiated with the same dose over a longer time scale, while tumors are treated with similar effectiveness. In other words, for tumors or other diseased tissue, a critical factor for treatment is total radiation dose as opposed to dose rate, whereas for healthy tissue, dose rate is a factor in reducing damage where none is desired. In this example, knowing the characteristics of the diseased tissue to be treated in the patient, the characteristics of the healthy tissue adjacent to the diseased tissue, the capabilities of the system delivering the radiation, the RBE of the radiation on the diseased tissue and the healthy tissue, the target dose and/or dose distribution to be applied, the dose calculation engine breaks the disease tissue—for example, a target volume—to be treated into voxels, determines the dose of radiation to be applied to each voxel, and sets the rate at which that dose is to be delivered. For example, the dose calculation engine may determine to apply to each voxel a dose of radiation that exceeds one (1) Gray-per-second for a duration of less than five (5) seconds. For example, the dose calculation engine may determine to apply to each voxel a dose of radiation that exceeds one (1) Gray-per-second for a duration of less than 500 ms. For example, the dose calculation engine may determine to apply to each voxel a dose of radiation that is between 40 Gray-per-second and 120 Gray-per-second for a duration of less than 500 ms. The radiation may be applied column-by-column as described, for example, with respect to FIGS. 12 to 19 or 33 to 42 , thereby reducing damage to healthy tissue through which the radiation travels to reach the target. In some implementations, ultra-high dose rate radiation may be applied to the entire target at once, for example, by scattering the radiation across the target, changing the energy as described with respect to FIGS. 12 to 19 or 33 to 42 while the radiation is stationary, and using a bolus to limit exposure of healthy tissue to the radiation.

In some implementations, the dose calculation engine may look at a time scale over which dose is to be delivered and apply one or more weights to individual doses in an attempt to adjust the RBE of the radiation. For example, the dose calculation engine may be configured to apply a weighting factor to a dose to a voxel to adjust the RBE based on a duration over which the dose is to be applied. As noted, biology may affect how doses of radiation are deposited and how tissues react to the doses. Weighting factors may be applied to counteract these biological effects. The weighting factors produce an equivalent dose which, as explained previously, has been adjusted to account for the biological effects in order to deliver an amount of destructive radiation that can actually be absorbed by the patient. In an example, a weighting factor causes the dose to increase for a duration to produce an ultra-high dose rate or to increase an already ultra-high dose rate. In an example, a weighting factor causes a dose to decrease for a duration while still being an ultra-high dose rate or to decrease to a conventional dose rate.

An example module includes sequencer 1204 (or “optimizer”). Sequencer 1204 generates instructions for sequencing delivery of the doses based on the model. In some implementations, the sequencer is configured to generate instructions for sequencing delivery of doses in order to optimize the effective doses determined by the dose calculation engine. For example, the instructions may be executable by the control system to control the particle therapy system to provide the dosage specified to each voxel at the dose rate specified. Delivery of the dosage may be automatic or it may require input from a user. As previously explained, the sequencer is configured—for example, written or programmed—to sequence delivery of the doses based on information from the prediction model or other information provided, for example, by a technician. The sequence of doses may be intended to optimize—for example, to minimize—the time it takes to deliver doses and, therefore, may promote delivery of radiation at ultra-high dose rates. For example, the sequencer may be configured to sequence delivery of the doses based on one or more of the following, two or more of the following, three or more of the following, four or more of the following, five or more of the following, or all of the following: a structure of pulses of a particle beam produced by the particle accelerator, a maximum dose per pulse of the particle beam, a sweep time of a scanning magnet to move the particle beam, a time it takes to change an energy of the particle beam, a time it takes to move one or more energy-absorbing structures to change the energy of the particle beam, a strategy for regulating the doses, a time it takes to move a collimator for collimating the particle beam, a time it takes to configure the collimator, or a time it takes to control a range modulator to change a Bragg peak of particles in the particle beam. In this regard, operations such as these affect the times at which dose may be delivered. To achieve ultra-high dose rates, timing is a consideration as described herein. Accordingly, factors such as these are taken into account when determining where dose is to be delivered to an irradiation target in order to meet the time constraints necessary to achieve ultra-high dose rates and benefits thereof.

In some implementations, values may be determined for, or assigned to, all or some of the following: a structure of pulses of a particle beam produced by the particle accelerator, a maximum dose per pulse of the particle beam, a sweep time of a scanning magnet to move the particle beam, a time it takes to change an energy of the particle beam, a time it takes to move one or more energy-absorbing structures to change the energy of the particle beam, a strategy for regulating the doses, a time it takes to move a collimator for collimating the particle beam, a time it takes to configure the collimator, and a time it takes to control a range modulator to change a Bragg peak of particles in the particle beam.

The sequencer knows how dose is to be delivered—for example, in columns or spots and at an ultra-high dose rate—and determines the order in which to deliver doses based on calculations performed that take the foregoing values into account. For example, referring to FIG. 31 , overlapping voxels of a target are shown, including adjacent voxels 1205, 1206, 1207, and 1208. The sequencer may determine, based on its calculations, that it is possible to move a particle beam from voxel 1205 to voxel 1206 and still achieve ultra-high dose rates for all voxels in the target since the particle beam can then be moved to adjacent voxel 1207, to adjacent voxel 1208, and so forth. The sequencer may also determine, based on its calculations, that it is not possible to move the particle beam from voxel 1205 to voxel 1207 and still achieve ultra-high dose rates for all voxels in the target. This may be because it would take too much time to move or to reconfigure hardware in the system, such as the collimator or energy-absorbing plates, when the beam moves between non-adjacent voxels 1206 and 1208 without interrupting the particle beam. In other words, the sequencer has determined a treatment sequence that treats adjacent voxels in sequence at ultra-high dose rates, thereby reducing the amount of mechanical movements to reconfigure the system between treatment locations while maintaining the particle beam.

In some implementations, the sequencer may assign several different values to each of the following: a structure of pulses of a particle beam produced by the particle accelerator, a maximum dose per pulse of the particle beam, a sweep time of a scanning magnet to move the particle beam, a time it takes to change an energy of the particle beam, a time it takes to move one or more energy-absorbing structures to change the energy of the particle beam, a strategy for regulating the doses, a time it takes to move a collimator for collimating the particle beam, a time it takes to configure the collimator, a time it takes to control a range modulator to change a Bragg peak of particles in the particle beam. The sequencer may perform calculations that iterate through these different values to obtain an optimized sequence at which doses of radiation should be applied to meet a desired dose rate. Optimization may include obtaining the best sequence in terms of time and treatment or obtaining an improved sequence in terms of time and treatment.

By way of example, a cubic treatment volume, such as a tumor, approximately 4 cm×4 cm×4 cm is to be treated to 2 Gy. The treatment plan includes of 5 layers each having 25 spots; that is, 5 rows×5 columns for 125 total spots in the volume. The system delivers one pulse of protons every 1.3 ms. In this example, each spot must receive at least 4 pulses so the dose to that spot can be delivered accurately through active dose control of the charge in each pulse. The deepest layer requires 6 pulses because more charge is required there. The scanning magnet moves fast enough that it can move from one spot to an adjacent spot in less than 1.3 ms, so no additional time is required for beam scanning. Energy layer switching takes 50 ms in this example.

The following example treatment plan excerpt is implemented using layer-by-layer treatment such as that described with respect to FIG. 1 . If the treatment is arranged in layers from deepest layer (1) to shallowest layer (5):

-   -   Beam delivery begins at time t=0     -   Each spot in layer 1 takes 1.3 ms×6 pulses=7.8 ms to deliver     -   No time to move from spot to spot     -   Entire layer takes 7.8 ms×25 spots=195 ms.     -   50 ms to switch to next layer, beam delivery on next layer         begins at t=245 ms.     -   Each spot in layers 2 to 5 takes 4 pulses×1.3 ms=5.2 ms to         deliver. Each layer takes 5.2 ms×25 spots=130 ms.     -   Layer 2 beam delivery ends at t=325 ms.     -   Layer 3 beam delivery ends at t=505 ms.     -   Layer 4 beam delivery ends at t=685 ms.     -   Layer 5 beam delivery ends, total treatment ends at t=865 ms.         In the above example, 2 Gy was delivered to the entire volume in         865 ms for an average dose rate of 2.3 Gy/s, which is well below         an example “FLASH” dose such as 40 Gy/s under some definitions.         But, each spot in the deepest layer reached 2 Gy in about 7.8         ms, neglecting the dose that spills over into adjacent spots         from each pulse. That is a dose rate of 256 Gy/s for those         spots. As dose is delivered to the deepest layer, dose is also         delivered to the shallower layers. So. each spot in the         shallowest layer received dose over almost the entire 865 m/s         and, as a result, experiences a lower dose rate than 256 Gy/s.

The following example treatment plan excerpt is implemented using column-by-column treatment such as that described with respect to FIG. 2 . If the same amount of treatment described in the preceding paragraph were to be rearranged into 25 columns instead of 5 layers, with each column being 5 spots deep:

-   -   Beam delivery begins at t=0     -   The spot in layer 1 takes 7.8 ms to deliver     -   50 ms to switch to the next shallower depth     -   Layer 2 spot beam delivery begins at 57.8 ms     -   Layer 3 spot beam delivery begins at 113 ms     -   Layer 4 spot beam delivery begins at 168.2 ms     -   This column completes at 223.4 ms     -   Treatment completes at 223.4 ms×25 columns=5.6 s.

This treatment results in a longer treatment time overall, but each column experiences a dose rate of 2 Gy/223.4 ms=9 Gy/s. This a higher dose rate, but may not be a FLASH dose rate under some definitions for every part of every column. But, assume an increase in the maximum proton charge per pulse so that with the same number of pulses it is possible to reach 10 Gy instead of 2 Gy. In this case, the dose rate for the layer-by-layer treatment examples goes up to 11.5 Gy/s. In this case, every voxel in the column-by-column treatment example is delivered dose at a rate of 45 Gy/s. Also, the layer switching time is decreased from 50 ms to 25 ms. In this example, each column in the column delivery takes 123.4 ms instead of 223.4 ms. In this example, the columnar dose rates for the lower maximum pulse charge is 16.3 Gy/s, while the columnar dose rates for the high maximum pulse charge is 81.5 Gy/s for every voxel in the treatment volume. A dose rate of 81.5 Gy/s for 123.4 ms qualifies as a FLASH dose rate under most definitions of FLASH.

Referring to FIG. 11 , the control system may be configured—for example, programmed—to implement the treatment plan for a target, such as tumor in the patient. As explained previously, the treatment plan may specify parameters including the dose of particle beam (for example, equivalent doses) to deliver and the rates (for example, an ultra-high dose rate or a standard dose rate) at which doses should be delivered to voxels in a patient. The treatment plan may also specify the locations at which dosed are to be delivered to the target and sequences at which parts of the target are to be treated. For example, referring to FIGS. 1 and 2 , the parts of the target may be columns or layers as described herein. Initially, the control system may control a particle accelerator—in this example, synchrocyclotron 310—to generate (1101) a particle beam having specified parameters, including beam current and intensity. In some implementations, the beam current of the particle beam is 100 nanoamperes (nA) of current or less. In some implementations, the beam current of the particle beam is 50 nA of current or less. Levels of beam current on the order of nanoamperes may reduce risks of injury to the patient, may reduce risks of damage to the accelerator or other electronics in the treatment room, or may reduce risks of both such injury and damage.

The intensity of the particle beam may also be controlled (1102), or modulated, to control or to change the dose applied to the target at different particle beam energies. Thus, intensity-modulated proton therapy (IMPT) may be delivered using the techniques described herein. In some implementations, the same irradiation target may be treated using beams having different or the same intensities from multiple different angles either at FLASH dose rates or at dose rates lower than FLASH dose rates. For example, an irradiation target may be treated at FLASH or non-FLASH dose rates by delivering radiation by columns at different angles. In such examples, because the radiation is delivered at different angles, healthy tissue that is not being treated may be subjected to radiation only once.

The beam intensity is based, at least in part, on the number of particles in the particle beam. For example, the beam intensity may be defined by the number of particles in the particle beam. The intensity of the particle beam may change from spot to spot of the particle beam. Additionally, the intensity of one spot of the particle beam may be independent of the intensity of one or more other spots of the particle beam, including immediately adjacent spots. Accordingly, in some examples, any spot in a three-dimensional volume may be treated to an arbitrary dose independent of the dose to one or more adjacent spots. The control system may control particle beam intensity using one or more techniques.

In an example technique, the intensity of the particle beam can be controlled by varying the time duration of the pulses of particles obtained from the plasma column. In more detail, the RF voltage sweeps from a starting (e.g., maximum) frequency (e.g., 135 megahertz (MHz)) to an ending (e.g., minimum) frequency (e.g., 90 MHz). The particle source is activated for a period of time during the RF sweep to produce a plasma column. For example, in some implementations, the particle source is activated at 132 MHz for a period of time. During that time, particles are extracted from the plasma column by the electric field produced by the RF voltage. The particles accelerate outwardly in expanding orbits as the RF voltage frequency drops, keeping pace with the decreasing magnetic field and increasing relativistic mass until the particles are swept out at a time (e.g., about 600 microseconds) later. Changing the duration for which the particle source is activated changes the width of the pulse of particles that are extracted from the plasma column during a frequency sweep. Increasing the pulse width causes an increase in the amount of particles extracted and thus an increase in the intensity of the particle beam. Conversely, decreasing the pulse width causes a decrease in the amount of particles extracted and thus a decrease in the intensity of the particle beam.

In another example technique, the intensity of the particle beam can be controlled by changing a voltage applied to cathodes in the particle source. In this regard, the plasma column is generated by applying a voltage to two cathodes of the particle source and by outputting a gas, such as hydrogen (H₂), in the vicinity of the cathodes. The voltage applied to the cathodes ionizes the hydrogen and the background magnetic field collimates the ionized hydrogen to thereby produce the plasma column. Increasing the cathode voltage causes an increase in the amount of ions in the plasma column and decreasing the cathode voltage causes a decrease in the amount of ions in the plasma column. When more ions are present in the plasma column, more ions can be extracted during the RF voltage sweep, thereby increasing the intensity of the particle beam. When fewer ions are present in the plasma column, fewer ions can be extracted during the RF voltage sweep, thereby decreasing the intensity of the particle beam.

In another example technique, the intensity of the particle beam can be controlled by varying the amount of hydrogen supplied to the particle source. For example, increasing the amount of hydrogen supplied to the particle source results in more opportunity for ionization in the plasma column in response to the cathode voltage. Conversely, decreasing the amount of hydrogen supplied to the particle source results in less opportunity for ionization in the plasma column in response to the cathode voltage. As noted above, when more particles are present in the plasma column, more particles are extracted during the RF voltage sweep, thereby increasing the intensity of the particle beam. When fewer particles are present in the plasma column, fewer particles are extracted during the RF voltage sweep, thereby decreasing the intensity of the particle beam.

In another example technique, the intensity of the particle beam can be controlled by varying the magnitude of the RF voltage used to extract particles from the plasma column. For example, increasing the magnitude of the RF voltage causes more particles to be extracted from the plasma column. Conversely, decreasing the magnitude of the RF voltage causes fewer particles to be extracted from the plasma column. When more particles are extracted, the particle beam has a greater intensity than when fewer particles are extracted.

In another example technique, the intensity of the particle beam can be controlled by varying the starting time during the frequency sweep at which the particle source is activated and, thus, during which particles are extracted. More specifically, there is a finite window during the frequency sweep during which particles can be extracted from the plasma column. In an example implementation, the frequency sweeps from about 135 MHz to about 90 MHz at a substantially constant rate. In this example, particles can be extracted at about the beginning of the downward slope between starting and ending frequencies, e.g., between 132 MHz and 131 MHz respectively, and the particle source can be activated for a period of time, e.g., for about 0.1 microseconds (μs) to 100 μs (e.g., 1 μs to 10 μs or 1 μs to 40 μs). Changing the frequency at which the particle source is activated affects the amount of particles that are extracted from the particle beam and therefore the intensity of the particle beam.

In another example technique, pulse blanking may be used to control the intensity of the particle beam. In this regard, the RF frequency sweep is repeated a number of times per second (e.g., 500 times/second). The particle source could be activated for each frequency sweep (e.g., every 2 ms). Pulse blanking reduces the number of particles extracted from the particle beam by not activating the particle source during every frequency sweep. To achieve maximum beam intensity, the particle source may be activated every frequency sweep. To reduce beam intensity, the particle source may be activated less frequently, e.g., every second, third, hundredth, etc. sweep.

In another example technique, the intensity of the particle beam can be controlled by applying a DC bias voltage to one or more dees used to apply the RF voltage to the particle accelerator cavity. In this regard, the particle accelerator includes an active dee plate that is a hollow metal structure having two semicircular surfaces that enclose a space in which the protons are accelerated during their rotation around the cavity enclosed by the magnet yokes. The active dee is driven by an RF signal that is applied at the end of an RF transmission line to impart an electric field into the space. The RF field is made to vary in time as the accelerated particle beam increases in distance from the geometric center. A dummy dee may include a rectangular metal wall with a slot that is spaced near to the exposed rim of the active dee. In some implementations, the dummy dee is connected to a reference voltage at the vacuum chamber and magnet yoke.

Applying RF voltage in the presence of a strong magnetic field can cause multi-pactoring, which can reduce the magnitude of the RF field and, in some cases, cause an electrical short. To reduce the amount of multi-pactoring, and thereby maintain the RF field, DC (direct current) bias voltage may be applied to the active dee and, in some implementations, also to the dummy dee. In some implementations, the differential DC bias voltage between the active dee and dummy dee may be controlled to reduce multi-pactoring and thereby increase beam intensity. For example, in some implementations, there may be a 50% differential between the DC bias voltage on the active dee and dummy dee. In an example implementation, there is a −1.9 KV DC bias voltage applied to the dummy dee and there is a −1.5 KV DC bias voltage be applied to the active dee.

In another example technique, the intensity of the particle beam can be controlled by controlling the rate at which the RF voltage is swept—for example, the slope of the decrease. By decreasing the slope, it is possible to increase the amount of time during which particles can be extracted from the plasma column. As a result, more particles can be extracted, thereby increasing the intensity of the particle beam. The converse is also true, e.g., by increasing the slope, the amount of time during which particles can be extracted from the plasma column can be decreased, which can result in a decrease in particle beam intensity.

Implementations of the foregoing techniques for controlling the particle beam intensity are described in U.S. Pat. No. 9,723,705 entitled “Controlling Intensity Of A Particle Beam”, the contents of which are incorporated herein by reference.

The control system may also control (1103) the spot size of the particle beam. As indicated above, one or more scattering devices may be moved into the path of the particle beam to change its spot size. Motors may be used to control movement of the scattering devices. The motors may be responsive to commands from the control system based on instructions in the treatment plan. In some implementations, the native spot size of the synchrocyclotron is the smallest spot size that is produced by the system. Since beam intensity is also a function of spot size, this spot size also produces the greatest beam intensity. In some implementations, the spot size that is producible by the system is less than 2 millimeters (mm) sigma. In some implementations, the spot size that is producible by the system is at least 2 mm sigma. In some implementations, the spot size that is producible by the system is between 2 mm sigma and 20 mm sigma. In some implementations, the spot size that is producible by the system is greater than 20 mm sigma. In some implementation, operation 1103 may be omitted.

The control system controls (1104) the scanning magnet to move the particle beam in accordance with the treatment plan to a path 24 through target 21, as shown in FIG. 2 for example. Controlling the scanning magnet may include controlling the current through the coils of the scanning magnet (FIGS. 6 and 7 ) that control movement of the particle beam in the Cartesian X dimension, controlling the current through coils of the scanning magnet that control movement of the particle beam in the Cartesian Y dimension, or both. At that location, the system delivers an ultra-high dose rate of radiation to a column that extends along the beam path through the target. In this example, the column includes interior portions of the target that are located along a direction 29 of the particle beam (FIG. 2 ). Column 25 is three dimensional in that it extends radially from the center of the beam spot to a perimeter of the spot and the column extends downward through the target. In some implementations, the column extends through the entirety of the target as shown in FIG. 2 . In some implementations, the column extends only part-way through the target. In some implementations the column is entirely within an interior of the target. In some implementations, the column starts at one surface of the target and extends to an interior of the target but does not reach the other surface of the target. In some implementations, parts of adjacent columns overlap.

The column is treated (1105) using an ultra-high dose rate of radiation. Examples of ultra-high dose rates of radiation are described herein and include, but are not limited to, 1. Gray-per-second or more for a duration of less than 5 s. The control system controls the energy of the particle beam while the particle beam is stationary so that the particle beam treats the column in the target. Treating the column in the target includes changing the energy of the particle beam so that, for each change in energy a majority of a dose of protons in the particle beam (its Bragg peak) deposits at a different depth within the target. As described herein, the energy of the particle beam may be changed by moving structures, which may be made of boron carbide, into or out of the path of the particle beam, as shown in the examples of FIGS. 12 to 19 and 33 to 42 . All or some of the operations of FIG. 11 may be repeated to treat different columns on an irradiation target. For example operations 1102, 1103, 1104, and 1105 may be repeated for each column to be treated on an irradiation target.

In implementations described below that use a variable-energy synchrocyclotron (or other type of variable energy particle accelerator), the energy of the particle beam may be changed by changing the current through the main coils of the synchrocyclotron. In some implementations, the energy of the particle beam is changed by moving structures, such as the energy-absorbing plates of range modulator 460, into and out of the path of the particle beam. In this regard, since the treatment plan specifies the locations of the columns on the target, the energy-absorbing plates of the range modulator may be pre-positioned proximate to those locations so as to reduce the time it takes for those plates to move into and out of position. Referring to FIG. 12 , for example, plates 500—which may be made from pure boron carbide or a boron carbide composite, for example—may be positioned proximate to column 501 in target 503 before treatment of column 501 with radiation begins. The plates may be moved from that location into the particle beam, thereby reducing the distance that the plates need to travel. That is, plates 500 may be configured to retract fully into the range modulator. The plates may be extended partially or fully prior to treatment and, as a result, need not travel from their fully retracted position in order to reach the path of the particle beam.

One or more of the plates may be controlled to move into and out of the path of the particle beam to change the energy of the particle beam, as noted. In an example, each of the one or more plates is movable into or out of the path of the particle beam in a duration of 100 ms or less. In an example, each of the one or more plates is movable into or out of the path of the particle beam in a duration of or less. In an example, each of the one or more plates is movable into or out of the path of the particle beam in a duration of 20 ms or less. Use of linear motors, as described previously, may promote rapid movement of the plates, although electrical motors may be used as well. In this example, rapid movement includes movement on the order of tens of milliseconds.

One or more of the plates may be moved into and out of the path of the particle beam based on sequences defined in the treatment plan. For example, referring to FIGS. 12, 13, 14, and 15 , a particle beam 504 is positioned by the scanning system to treat column 501 of target 503 at an ultra-high dose rate. In this example, to treat progressively shallower portions of column 501, treatment initially is performed with no plate in the path of the particle beam. This is shown in FIG. 12 . The deepest part 502 of column 501 therefore is treated. In FIG. 13 , plate 500 a proceeds into the path of particle beam 504 along the direction of arrow 505 to reduce the energy of the particle beam. In this plate configuration, the second deepest part 506 of column 501 is treated. In FIG. 14 , plate 500 b also proceeds into the path of particle beam 504 along the direction of arrow 505 to reduce further the energy of the particle beam. In this plate configuration, the third deepest part 508 of column 501 is treated. In FIG. 15 , plate 500 c also proceeds into the path of particle beam 504 along the direction of arrow 505 to reduce further the energy of the particle beam. In this plate configuration, the shallowest part 510 of column 501 is treated. By changing the energy of particle beam 504 while particle beam 504 is stationary, the entirety of column 501 may be delivered ultra-high dose rate radiation. Examples of ultra-high dose rates are provided herein.

The particle beam may be directed by the scanning magnet to a new path through the target to treat a different column of target 503. The different column may be immediately adjacent to column 501 or may not be immediately adjacent to column 501. In some implementations, spots of the beam may overlap in part. For example, referring to FIGS. 16, 17, 18, and 19 , a particle beam 604 is positioned by the scanning system to treat column 601 of target 503 at an ultra-high dose rate. In this example, to treat progressively deeper portions of column 601, treatment initially is performed with all plates 500 a, 500 b, and 500 c in the path of the particle beam. This is shown in FIG. 16 . The shallowest part 602 of column 601 therefore is treated first. In FIG. 17 , plate 500 c moves out of the path of particle beam 604 along the direction of arrow 605 to increase the energy of the particle beam. In this plate configuration, the second shallowest part 602 of column 601 is treated. In FIG. 18 , plate 500 b also moves out of the path of particle beam 604 along the direction of arrow 605 to increase further the energy of the particle beam. In this plate configuration, the third shallowest part 608 of column 601 is treated. In FIG. 19 , plate 500 c also moves out of the path of particle beam 604 along the direction of arrow 605 to increase further the energy of the particle beam. In this plate configuration, the deepest part 610 of column 601 is treated. By changing the energy of particle beam 604 while particle beam 604 is stationary, the entirety of column 601 may be delivered ultra-high dose rate radiation.

In some implementations, the plates need not be sequenced in order to treat a column. For example, plate 500 a could be moved into the path of the particle beam first, followed by plate 500 c, followed by plate 500 b.

During delivery of ultra-high dose rate radiation to column 501 or 601, the intensity of particle beam 504 or 604 may be changed as necessary in order to deliver the ultra-high dose rate radiation specified in the treatment plan. Notably, the particle beam is stationary during delivery of the ultra-high dose rate radiation to each column. For example, while the ultra-high dose rate radiation is being delivered to different depths within the column, the path of the particle beam does not change relative to the target and the particle beam does not move. After the ultra-high dose rate radiation is delivered to the column, the particle beam is directed on a new path through the target in accordance with the treatment plan. Ultra-high dose rate radiation is then applied at that new path in accordance with the treatment plan in the same manner as described with respect to FIG. 11 . This process is repeated until all of the target is treated using the ultra-high dose rate radiation or until a designated part of the target is treated using the ultra-high dose rate radiation. In some implementations, the columns may be parallel as shown in the figures, with some overlap in some implementations. In some implementations, at least some of the columns may not be in parallel resulting in overlap. In some implementations, sets of columns may be applied to the same target or micro-volume from different angles, thereby treating the target multiple times with radiation while preventing healthy tissue from being impacted by radiation more than once.

In some implementations, the particle beam is never again directed along paths that have already been treated using the ultra-high dose rate radiation. For example, the particle beam steps from path to path through target 503. In this example, each column extending into the target along a path is treated using the ultra-high dose rate radiation only once. Columns are not revisited and treated again. By treating columns only once using ultra-high dose rate radiation, healthy tissue above, and in some cases below, the target is less susceptible to damage from the radiation. Notably, however, the example systems described herein are not limited to treating each column only once using the ultra-high dose rate radiation. For example, in some implementations, each column may be revisited any appropriate number of times and subjected to one or more additional doses of ultra-high dose rate radiation. Furthermore, the example systems described herein are not limited to treating each column using only ultra-high dose rate radiation. For example, columns of a target may be treated as described herein using dose rates of radiation that are less than what would be considered an ultra-high dose rate. For instance, columns of a target may be treated as described herein using dose rates of radiation such as 0.1 Gray-per-second for a duration of one or more minutes. In some implementations, column-by-column treatment such as that shown in FIG. 2 may be combined with layer-by-layer treatment such as that shown in FIG. 1 . For example, the target may be treated column-by-column followed by layer-by-layer or treated layer-by-layer followed by column-by-column. In some implementations, part of the target may be treated column-by-column and part of the target may be treated layer-by-layer in each case with ultra-high dose rate radiation or less.

In some implementations, energy-absorbing plates of the range modulator may be sequenced differently for different columns on the target in order to reduce treatment time. For example, for a column 501, the plates may be moved sequentially into the particle beam as explained with respect to FIGS. 12 to 15 . Then, the particle beam may be directed to treat an adjacent—or other—column 601 of the target. If the plates already cover that path of the particle beam, they may be moved sequentially out of the path of the particle beam as described with respect to FIGS. 16 to 19 . If the plates do not already cover that path of the particle beam, the plates may be moved together to cover that path of the particle beam and then moved sequentially out of the path of the particle beam. Accordingly, for a first column, the plates may be moved sequentially to treat progressively shallower portions—for example, layers—of the first column. For a second column that is adjacent to the first column, the plates the plates may be moved sequentially to treat successively deeper portions—for example, layers—of the second column. This process may be repeated throughout the target for adjacent paths of the particle beam. In some implementations, movements of the plates may be incremental in the beam field; for example, based on the spot size (e.g., on the order of millimeters) rather than from their fully retracted position. For example, the plates may be moved from particle beam path to adjacent particle beam path rather than being fully retracted and extended for each column.

In some implementations, the energy-absorbing plates are movable across all or part of the beam field. In some examples, the beam field is the maximum extent that the beam can be moved across a plane parallel to the treatment area on a patient. One or more of the plates may track the particle beam as it moves from particle beam to adjacent particle beam. For example, one or more of the plates may move along with movement of the particle beam such that the particle beam passes through one or more of the plates while the plates move.

In some implementations, a dose of radiation that is less than an ultra-high (or FLASH) dose rate radiation may be applied to the target layer-by layer using an energy degrader having structures such as plates, polyhedra, or curved three-dimensional shapes that are made of boron carbide. For example, referring to FIG. 1 , an entire layer 10 of a target 11 may be treated using a particle beam 12 having an energy sufficient to deliver dose to layer 10 by moving the particle beam across the layer along the directions of arrows 15. The energy degrader may then be reconfigured—for example, a plate made of boron carbide may be moved out of the beam path to increase an energy level of the particle beam. Then a different layer 16 of the target 11 may be treated in the same manner using a particle beam having a different energy sufficient to deliver dose to layer 16, and so on.

In some implementations, FLASH doses of radiation may be delivered along a single column, with the beam direction fixed at a single spot at an isocenter of the particle accelerator. In some implementations, FLASH doses of radiation may be delivered using slightly larger localized volumes—referred to as micro-volumes—rather than columns aimed at a single spot. A micro-volume may be a voxel, part of a voxel, or include multiple voxels as specified in the treatment plan. FIGS. 33 to 42 show an example of delivery of radiation by column using FLASH dose rates to micro-volumes of an irradiation target. Examples of FLASH dose rates are described herein. In some implementations, delivery of radiation by column to the micro-volumes of FIGS. 33 to 42 may be at non-FLASH dose rates or combined FLASH dose rates and non-FLASH dose rates.

FIG. 33 shows an example of part 1400 of an irradiation target, such as a tumor in a patient. Part 1400 is broken into four micro-volumes 1401, 1402, 1403, and 1404. Although cubical micro-volumes are shown, the micro-volumes may have any appropriate shape, such as three-dimensional orthotopes, regular curved shapes, or amorphous shapes. In this example, each micro-volume is treated through delivery of radiation by column in the manner described herein, for example with respect to FIGS. 12 to 19 . For example, column depths of a micro-volume may be treated with radiation by using energy degrader plates to change the beam energy or by controlling a variable-energy synchrocyclotron to change the beam energy. After an individual micro-volume has been treated, the next micro-volume is treated, and so forth until the entire irradiation target has been treated. Treatment of the micro-volumes may be in any appropriate order or sequence.

In the example of FIGS. 33 to 42 , only eight columns 1405 are shown. However, any appropriate number of columns may be treated per micro-volume. In some examples 10 to 20 spots, and thus columns, may treat a micro-volume. In addition, although each spot corresponds to a column of radiation, only the front columns are shown in the figures for clarity. Furthermore, although the example described herein treats the micro-volumes from the most deep part of the column to the most shallow part of the column, that need not be the case. For example, energy degrader plates may be controlled to treat one micro-volume from the most deep part of columns to the most shallow part of the columns and then treat the neighboring micro-volume from the most shallow part of the columns to the most deep part of the columns and so forth, as described with respect to FIGS. 12 to 19 . In other examples, different column depths may be treated non-sequentially.

In FIG. 33 , the deepest parts 1407 of columns 1405 are treated. Treated parts of the columns are shaded and untreated parts are not shaded, as is the convention herein. In FIG. 34 , the next deepest parts 1408 of columns 1405 are treated. In FIG. 35 , the next deepest parts 1409 of columns 1405 are treated. In FIG. 36 , the next deepest parts 1410 of columns 1405 are treated. In FIG. 37 , the shallowest parts 1411 of columns 1405 are treated, thereby completing treatment of micro-volume 1401. In this regard, although the columns are separated for clarity, the columns may actually overlap at least in part as is the case with respect to FIGS. 12 to 19 to ensure that the entire micro-volume is treated with radiation.

After micro-volume 1401 is treated, the next micro-volume 1402 is treated in a similar manner. In FIG. 38 , the deepest parts 1417 of columns 1415 are treated. In FIG. 39 , the next deepest parts 1418 of columns 1415 are treated. In FIG. 40 , the next deepest parts 1419 of columns 1415 are treated. In FIG. 41 , the next deepest parts 1420 of columns 1415 are treated. In FIG. 42 , the shallowest parts 1421 of columns 1415 are treated, thereby completing treatment of micro-volume 1402. As was the case above, although the columns are separated for clarity, the columns may actually overlap at least in part as is the case with respect to FIGS. 12 to 19 to ensure that the entire micro-volume is treated with radiation.

After micro-volume 1402 is treated, the remaining micro-volumes may be treated in a similar manner. The micro-volumes may be treated in any order or sequence and using any appropriate number and placement of columns. In addition, as described herein, individual columns may be treated using different beam intensities. These intensities may vary from column-to-column, from micro-volume-to-micro-volume or both from column-to-column and from micro-volume-to-micro-volume. Furthermore, each micro-volume may be treated from multiple different angles as part of intensity-modulated proton therapy treatment (IMPT).

In an example, plots of FIGS. 43A and 43B show the results of Monte Carlo simulations that calculate radiation dose delivered to a treatment volume as well as the time it takes for each voxel in that dose calculation to reach the final dose. In an example, applying performance modifications to some parameters of a synchrocyclotron—for example, 10 ms or less layer switching time instead of 50 ms layer switching time, increasing the beam current, and enhancing pulse-pulse stability—spots delivered on a cube that is 3 cm on each side can be delivered with every part of the treatment volume receiving its dose in less than 500 ms. These small cubes were not strictly delivered in columns where each energy layer has a single spot, but rather in micro-volumes where each layer has a few (e.g., 10 to 20) spots. In addition, collimation may be used to isolate one micro-volume from another, allowing these volumes to be delivered in a reasonable amount of total treatment time. For example, the configurable collimator described herein or any other appropriate collimating device, including standard multi-leaf collimators (MLC), may be used.

In some implementations, each micro-volume may be treated in the manner described with respect to FIGS. 12 to 19 . For example, the entirety of a column in a micro-volume may be treated before moving on to a next column in the same micro-volume. Once all columns are treated in a micro-volume, then treatment proceeds to the next micro-volume. There, treatment is repeated until all columns of the micro-volume are treated. Treatment then proceeds to the next micro-volume and so on until the entire irradiation target is treated. These implementations differ from the implementations of FIGS. 33 to 42 in which an entire depth—or micro-layer—of each column in a micro-volume is treated at once for every column in that micro-volume. Thereafter, treatment proceeds to the next depth and so forth until all columns in the micro-volume have been treated.

Delivering radiation at ultra-high dose (FLASH) rates to all or part of a column as described herein may be implemented to deposit doses of radiation in any random manner. For example, referring to FIG. 32 , an example column 1299 in a radiation target may be comprised of multiple depths. Each depth may comprise a micro-layer of the target that has about the diameter of a spot of the particle beam. Using delivery or radiation by column as described herein, radiation may be delivered to each of depths 1301, 1302, and 1303 at ultra-high dose (FLASH) rates. Doses may be delivered in any manner established by the treatment plan. For example, a higher dose of radiation may be applied to depth 1303 than to depths 1301 or 1302. In another example, the highest dose may be applied to depth 1303, the next highest dose may be applied to depth 1302, and the lowest dose may be applied to depth 1302. In another example, the highest dose may be applied to depth 1301, the next highest dose may be applied to depth 1303, and the lowest dose may be applied to depth 1302. Thus, doses may be applied without regard to—for example, independent of—the shape of a Bragg peak produced by summing the multiple doses. In other words, in some cases, the doses may not be configured to obtain a spread-out Bragg peak along a column of radiation delivered to an irradiation target at ultra-high dose (FLASH) rates or at lower dose rates.

In some implementations, one or more ridge filters or range modulator wheels may be added into the path of the particle beam to spread out—for example, to elongate—the Bragg peak of the particle beam. An elongated or spread-out Bragg peak is created by using a uniform depth-dose curve. That is, the dose is calibrated based on the depth in the tissue to which the dose is to be delivered in order to achieve an elongated Bragg peak that is flat or substantially flat. Referring to FIG. 32 , for example, to achieve a spread-out Bragg peak such as 1300 using delivery of radiation by column, a full (100%) dose may be applied to depth 1301 in column 1299 of an irradiation target for a period of time. Next, an 80% dose may be applied to depth 1302 for a period of time. Depth 1302 is up-beam (that is, more shallow) than depth 1301. Next, a 66% dose may be applied to depth 1303 for a period of time. Depth 1303 is up-beam (that is, more shallow) than depth 1302. This may be repeated until spread-out Bragg peak 1300 is achieved.

Motors may control movement of the one or more ridge filters or range modulator wheels into or out of the path of the particle beam. The motors may be responsive to command of the control system. Spreading out the Bragg peak of the particle beam may be used for both columnar treatment as shown in FIGS. 12 to 19 or layer-by-layer treatment as shown in FIG. 1 . In some implementations, the intensity of the particle beam may be increased using techniques such as those described herein when the Bragg peak is spread-out.

In some implementations, a range modulator wheel may be robotically controlled to move in two dimensions or in three dimensions within the beam field so as to track movement of the particle beam. For example, referring to FIG. 23 , the range modulator wheel may be robotically controlled to move in the Cartesian X dimension 918 and Z dimension 917 in the path of the particle beam. The range modulator wheel may have varying thicknesses and may spin to change the Bragg peak of the particle beam and thus the depth within the target at which a majority of the particles are deposited. In some implementations, the range modulator wheel may include steps that define its various thicknesses. In some implementations, the intensity of the particle beam may be controlled in order to control the dose delivered at each location on the range modulator wheel. This may be done in order to control depth-dose distributions.

As explained above, in some implementations, the scanning system does not include a configurable collimator. For example, in systems that include boron carbide in the energy degrader, the spot size may be small and precise enough to eliminate the need for a configurable collimator. However, in some implementations, the scanning system does include a configurable collimator. The configurable collimator may be controlled by the control system to trim the particle beam prior to the particle beam reaching the irradiation target. As also explained, the configurable collimator may be controlled to trim a stationary particle beam differently as the energy of that particle beam changes to treat different portions—for example, depths—of a column in a target. More specifically, the cross-sectional area of the particle beam—in other words, the spot size of the particle beam—may change as the particle beam passes through different amounts of tissue. To ensure that the size of the particle beam and thus the radius of the column being treated remains consistent throughout the length of the column, the configuration of the collimator may be changed to provide different amounts of trimming. In other words, the configuration of the configurable collimator may be changed in response to changes in the energy of the particle beam. That is, since beams of different energy penetrate different amounts of tissue, those beams may experience different amounts of dispersion and therefore may require different amounts of collimation to produce a regularly-shaped column such as a column having a cylindrical shape with a constant radius.

In some implementations, the configurable collimator contains generally flat structures, which are referred to as “plates” or “leaves”, and which are controllable to move into the beam or treatment area to block passage of some radiation and allow passage of other radiation. As explained above, there may be two sets of leaves that face each other. The sets of leaves are controllable to produce an opening of size and shape that is appropriate for treatment. For example, each set of leaves is configurable to define an edge that is movable into a path of the particle beam so that a first part of the particle beam on a first side of the edge is blocked by the leaves, and so that a second part of the particle beam on a second side of the edge is not blocked by the leaves and is allowed to pass to the treatment area. In some implementations the leaves are connected to, are part of, or include, linear motors—one per leaf—that are controllable to control movement of the leaves towards or away from the treatment area to define the edge.

In some implementations, the linear motors are controllable to configure a set of leaves to define a first edge and to configure another set of leaves to define a second edge that faces the first edge. The linear motors used with the configurable collimator may have configurations similar or identical to the linear motors used with the range modulator plates described with respect to FIG. 10 . For example, each of the linear motors may include a movable component and a stationary component. The stationary component includes a magnetic field generator to generate a first magnetic field. An example of a magnetic field generator includes two stationary magnets that are adjacent and spaced apart and that have their poles aligned. The movable component includes one or more coils to conduct current to produce a second magnetic field that interacts with the first magnetic field to cause the moveable component to move relative to the stationary component. For example, the movable component may be a coil-carrying plate between the two magnets that make up the stationary component. When current passes through the coil, that current produces a magnetic field that interacts with the magnetic field produced by the two magnets, and that causes the movable component (e.g., the current-carrying plate) to move relative to the two magnets. Because a leaf is attached to the movable component, the leaf moves along with the movable component. The linear motors of different leaves may be controlled to control movement of the leaves, and thus to define the edges of the configurable collimator described above.

As noted, in some implementations, a linear motor includes two magnets that are adjacent and spaced apart and that have their poles aligned, and a coil-carrying plate that is sandwiched between the two magnets and that moves relative to the two magnets. This configuration allows multiple linear motors to be arranged in a row, each in close proximity to the next, as may be required to control leaves of the configurable collimator. For example, in some implementations, the leaves are on the order of millimeters thick (e.g., five millimeters or less). Leaves of this thickness enable relatively high precision edges; however, leaves of this thickness can make implementation using conventional motors impractical in some cases. However, the linear motors described herein enable use of leaves having thicknesses of this magnitude. For example, the two stationary magnets shield the coil-carrying plate that moves between them, thereby controlling movement of the leaves. By shielding the coil-carrying plates from stray magnetic fields, it is possible to control movement of the plates even when multiple coil-carrying plates and corresponding stationary magnets are close proximity to each other.

In some implementations, the control system, which may be comprised of one or more processing devices, is programmed to control the linear motors to thereby control positioning of leaves to define an edge. For example, the control system may be controllable to output one or more control signals to control one or more of the linear motors to extend or to retract one or more of the leaves to define the edge. In some implementations, motion of the linear motors may be tracked using encoders. In some examples, encoders include electronic devices that are connected to a same assembly as the leaves and the linear motors. The encoders may include or more of laser sensors, optic sensors, or diode sensors. The encoders detect movement of the leaves, e.g., by detecting where markings or other indicia on the leaves, or on structures that are connected to and that move with the leaves, are located relative to the encoders. Information about locations of the leaves is fed back to the control system and is used by the control system to confirm the position of the leaves during operation and, in some implementations, to change their position. The encoders may be, or include, simple electronic sensors that are not as sensitive to neutron radiation as the processing devices above and that, therefore, may be located in the treatment room.

As noted previously, some implementations may not include a configurable collimator. In example implementations such as these, the particle beam passes through the energy degrader and to the patient without subsequent conditioning such as collimation. For example, in implementations where the structures—such as plates, polyhedra, or curved three-dimensional shapes—include boron carbide, the spot size of the beam may be reduced relative to the spot size of the beam produced using other materials in the energy degrader. In such cases, additional collimation may not be necessary to achieve the spot resolution needed to treat the irradiation target. As noted, in some implementations, a configurable collimator may be between the energy degrader and the patient. Example implementations of a configurable collimator that may be used are described with respect to FIGS. 20 to 25 .

FIG. 20 shows an example of a leaf 740 that may be used in the configurable collimator, although the configurable collimator is not limited to use with this type of leaf. The height 750 of the leaf is along the beam line (e.g., the direction of the particle beam). The length 752 of the leaf is along its direction of actuation into and out of the treatment area, and is based on the field size, or portion thereof, that the system can treat. The field size corresponds to the treatment area that the beam can impact. The width 753 of the leaf is the direction along which multiple leaves stack when actuated. Generally, the more leaves that are used, the higher the resolution of the aperture that can be produced, including for curved boundaries.

In FIG. 20 , leaf 740 includes a tongue and groove feature 755 along its side, which is configured to reduce inter-leaf leakage when multiple such leaves stack. In this example, the curved end 756 of leaf 740 is configured to maintain a surface tangent to the beam at all locations in the treatment area. However, the end of each leaf may be flat, not curved.

In some implementations, the configurable collimator leaves have a height that is sufficient to block at least the maximum beam energy (e.g., the maximum energy of the particle beam output by the accelerator). In some implementations, the configurable collimator leaves have a height that blocks less than the maximum beam energy. In some implementations, the configurable collimator leaves have lengths that are dictated not by the area of an entire treatment area, but rather by the area of a single beam spot (the cross-sectional area of the particle beam) or multiple beam spots.

FIG. 21 shows an example implementation of part a configurable collimator 800. Configurable collimator 800 includes leaves 801 having a height and made of a material, such as nickel, brass, tungsten, or other metal, sufficient to inhibit or prevent passage of radiation at a given energy. For example in some systems, a particle accelerator is configured to generate a particle beam having a maximum energy of 100 MeV (million electron-volts) to 300 MeV. Accordingly, in such systems, the leaves may be constructed to prevent passage of a beam having an energy of 100 MeV, 150 MeV, 200 MeV, 250 MeV, 300 MeV, and so forth. For example in some systems, a particle accelerator is configured to generate a particle beam having a maximum energy that exceeds 70 MeV. Accordingly, in such systems, the leaves may be constructed to prevent passage of a beam having an energy of 70 MeV or more.

Leaves 801 are mounted on carriages to control their movement relative to a treatment area of an irradiation target, such as a cross-sectional layer of a tumor in a patient. The movement is controlled to cause leaves 801 to cover some parts of treatment area 804, thereby preventing radiation from impacting those parts during treatment, while leaving other parts of treatment area exposed to the radiation. In the example implementation of FIG. 21 , there are fourteen leaves in total, seven on the left and seven on the right. In some implementations, there may be a different number of leaves, e.g., ten in total, five on the left and five on the right, twelve in total, six on the left and six on the right, and so forth.

In FIG. 21 , locations 802 represent centers of beam spots and thus the locations of columns in the target to which radiation is to be delivered. Circle 808 represents parts of a treatment boundary beyond which no radiation is intended to be delivered. Beam spots that are close to this boundary (e.g., within one standard deviation of the particle beam's profile) border healthy tissue. These spots may be trimmed (that is, blocked) by appropriate configuration and placement of leaves on the configurable collimator. An example of a beam spot to be trimmed is beam spot 811, having its center at location 806. As shown, leaves 801 are configured to block the portion of beam spot 811 that extends beyond circle 808 and into healthy tissue (or at least tissue not designated for treatment).

In an example implementation, on each of two separate carriages, there are five leaves that are about 5 mm in width and two leaves that are about in width. In some implementations, on each of two separate carriages, there are seven leaves, two of which each have widths that are three times or more the widths of each of five other leaves. Other implementations may contain different numbers, sizes, and configurations of leaves, and different numbers and configurations of carriages. For example, some implementations may include any number between five and fifty leaves per carriage, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 leaves (or more) per carriage.

The carriages can move both horizontally and vertically, as described herein. The leaves are also movable horizontally relative to each carriage into, and out of, the treatment area. In this way, the leaves are configurable to approximate the shape of the treatment boundary in the region near the area being treated (e.g., circle 811 or a portion thereof in this example).

The leaves may be moved vertically and/or horizontally between different columns to be treated so that the leaves are in appropriate positions when the beam is delivered to a particular column. As noted, the leaves may be reconfigured while the beam is stationary and based on beam energy to provide different configurations for different beam energies. As explained, the beam may disperse somewhat in tissue. The configurable collimator may be reconfigured as beam energy changes to maintain a regularly (e.g., cylindrically) shaped column.

FIGS. 22, 23, and 24 show an example implementation of a configurable collimator, including carriages 913, 914, 915 configured to hold, and to move, the leaves described above both vertically and horizontally relative to the treatment target. As shown, vertical movement includes movement in the Cartesian Z-dimension 917, and horizontal movement includes movement in the Cartesian X dimension 918 (with the Cartesian Y dimension being into, or out of, the page in FIG. 23 ). FIGS. 23 and 24 show parts of carriage housings as transparent in order to show components inside the housings; however, the housings are not actually transparent.

Carriage 913 is referred to herein as the primary carriage, and carriages 914 and 915 are referred to herein as secondary carriages. Secondary carriages 914, 915 are coupled to primary carriage 913, as shown in FIGS. 22 to 24 . In this example, secondary carriages 914, 915 each include a housing that is fixed to primary carriage 915 via a corresponding member 918, 919. In this example, primary carriage 913 is movable vertically (the Z dimension) relative to the irradiation target and relative to particle accelerator along tracks 920. The vertical movement of primary carriage 913 also causes the secondary carriages to move vertically. In some implementations, the secondary carriages move vertically in concert. In some implementations, vertical movement of each secondary carriage is independent of vertical movement of the other secondary carriage.

As shown in FIGS. 22 to 24 , each secondary carriage 914, 915 is connected to a corresponding rod or rail 922, 923, along which the secondary carriage moves. More specifically, in this example, motor 925 drives secondary carriage 914 to move along rod 922 towards or away from secondary carriage 915. Likewise, in this example, motor 926 drives secondary carriage 915 to move along rod 923 towards or away from secondary carriage 914. Control over movement of the primary and secondary carriages is implemented to position the leaves relative to the irradiation target, as described herein. In addition, the leaves themselves are also configured to move in and out of the carriages, as also described herein.

As shown in FIG. 24 , a motor 930 drives the vertical movement of primary carriage 913. For example, as shown in FIG. 24 , lead screw 931 is coupled to housing 932, which holds motors 925, 926 that drive corresponding secondary carriages 914, 915, and which is mounted on tracks 920. Lead screw 931 is coupled to, and driven vertically by, motor 930. That is, motor 930 drives lead screw 931 vertically (the Cartesian Z dimension). Because lead screw 931 is fixed to housing 932, this movement also causes housing 932, and thus secondary carriages 914, 915, to move along tracks 920, either towards or away from the irradiation target.

In this example implementation, as noted, seven leaves 935, 936 are mounted on each secondary carriage 914, 915. Each secondary carriage may be configured to move its leaves horizontally into, or out of, the treatment area. The individual leaves on each secondary carriage may be independently and linearly movable using linear motors in the X dimension relative to other leaves on the same secondary carriage. In some implementations, the leaves may also be configured to move in the Y dimension. Furthermore, the leaves on one secondary carriage 914 may be movable independently of the leaves on the other secondary carriage 915. These independent movements of leaves on the secondary carriages, together with the vertical movements enabled by the primary carriage, allow the leaves to be moved into various configurations. As a result, the leaves can conform, both horizontally and vertically, to treatment areas that are randomly shaped both in horizontal and vertical dimensions. The sizes and shapes of the leaves may be varied to create different conformations. For example, the sizes and shapes may be varied to treat a single beam spot and, thus, a single column. In some implementations individual leaves on each secondary carriage may be independently and linearly movable using electric motors that drive lead screws in the X dimension relative to other leaves on the same secondary carriage.

The leaves may be made of any appropriate material that prevents or inhibits transmission of radiation. The type of radiation used may dictate what material(s) are used in the leaves. For example, if the radiation is X-ray, the leaves may be made of lead. In the examples described herein, the radiation is a proton or ion beam. Accordingly, different types of metals or other materials may be used for the leaves. For example, the leaves may be made of nickel, tungsten, lead, brass, steel, iron, or any appropriate combinations thereof. The height of each leaf may determine how well that leaf inhibits transmission of radiation.

In some implementations, the leaves may have the same height, whereas in other implementations, some of the leaves may have heights that are different from heights of others of the leaves. For example, a set of leaves may each be 5 mm in height. However, any appropriate heights may be used. For example, leaves 935, 936 may have any of the following (or other heights): 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 3 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, and so forth. The leaves may have any combination of the foregoing heights. In addition, each of the leaves may have a different height than one or more others of the leaves.

In some implementations, the leaves have heights that are enough not only to fully stop a particle beam at the maximum expected proton energy (e.g., 3.3 cm of Tungsten at 230 MeV or, e.g., 5.2 cm of nickel), but also to have enough extra material to prevent proton transmission between the leaves. This material may have a tongue and groove structure as shown in FIG. 20 , or a similar configuration. The leaf ends may be configured to include curved or tapered surfaces to enhance delivered penumbra for proton beams of various divergence.

In some implementations, there may be more than one primary carriage and corresponding motors and rails. For example, a first primary carriage may control vertical movement of a first secondary carriage, and a second primary carriage may control vertical movement of a second secondary carriage. Therefore, in such implementations, the two secondary carriages can be moved independently in the vertical dimension, if desired. In any case, the primary carriage may be computer controlled. For example, executable instructions are stored in computer memory (e.g., one or more non-transitory machine-readable storage media), and executed by one or more processing devices to control the movement. Control may be performed with, or without, user input during treatment.

As explained, each secondary carriage 914, 915 includes a corresponding motor to control horizontal carriage movement, as described above. In some implementations, all leaves on a single carriage are independently movable using linear motors—with one linear motor controlling each leaf. Each leaf may be controlled by a linear motor of the type described in FIG. 10 to create an edge to block at least some radiation from reaching the patient, e.g., to trim one or more spots produced by the particle beam. As noted, a linear motor used in the configurable collimator may have the same structure and function as a linear motor used with the range modulator. In this case, however, the collimator leaf is attached to the linear motor instead of an energy-absorbing plate. Each linear motor drives its corresponding leaf linearly to reach its position in a configured edge.

In the example implementations described above, each leaf is independently actuated using a separate, and independently-controllable, linear motor such that any appropriate shape can be traced with a leaf configuration. It may be, however, that such flexibility is not required to achieve acceptable edge conformality. The leaves could be mechanically constrained with the ability to achieve only a finite number of configurations. For example, the leaves could be restricted to arrangements that put them in a vertical line, forward diagonal shape, backward diagonal shape, concave shape, convex shape, or any other achievable shape. In this way, flexibility could be traded for mechanical simplicity.

In some cases, better beam performance (penumbra or edge sharpness) results when the particle beam is tangent to the surface of a leaf edge. However, since the beam effectively originates from a single point source, the angle with which it passes through the plane of the configurable collimator changes as the beam is moved away from the center of the field. For this reason, leaves may have curved edges, as shown in FIG. 20 , so that the edges can always be placed a location that makes them tangent to the particle beam. In an example implementation of the configurable collimator, the tracks on which both primary and secondary carriages move are curved so that flat leaf edges can be used in lieu of curved leaf edges, and so that the flat but remain tangent to the particle beam.

To summarize, in some implementations, the configurable collimator may have a relatively small size, at least in part due to the linear motors described herein. Thus, in contrast to standard multi-leaf collimators, an example configurable collimator may therefore be used to trim a fraction of a treatment area at one time, e.g., an area that is less than the entire treatment area and that is about equal to one spot size, two spot sizes, three spot sizes, four spot sizes, five spot sizes, and so forth. Thus, in some implementations, the configurable collimator may be small enough to trim a single spot at once and may be large enough to trim several spots in one position, but not the entire field without moving. As noted, the ability to trim a single spot may be used to maintain a regular shape of a treatment column as the energy of the particle beam used to create that column varies.

The scanning system may include the configurable collimator described herein, which is placeable relative to the irradiation target to limit the extent of the particle beam. For example, the configurable collimator may be placed in the beam path down-beam of the energy degrader and before the particle beam hits the treatment area of the irradiation target. The configurable collimator is controllable by the control system and in accordance with the treatment plan to allow the particle beam to pass therethrough and then hit certain parts of the treatment area, while preventing the particle beam from hitting other parts of the patient. FIG. 25 depicts placement of an implementation of the configurable collimator 970 relative to a patient 971. The direction of beam 971 a is also shown.

An example of a configurable collimator that may be used is described in U.S. Patent Publication No. 2017/0128746 entitled “Adaptive Aperture”, the contents of which are incorporated herein by reference.

FIGS. 26 and 27 show parts of an example of a proton therapy system 1082 containing a particle accelerator mounted on a gantry. Because the accelerator is mounted on the gantry it is in or adjacent to the treatment room. The particle accelerator may be the synchrocyclotron of FIG. 3 ; however, the system is not limited to use with synchrocyclotrons. The gantry and the particle accelerator may be controlled, along with the scanning system, in accordance with the treatment plan to treat columns of an irradiation target using ultra-high dose rate radiation in the manner described herein. In some implementations, the gantry is steel and has two legs (not shown) mounted for rotation on two respective bearings that lie on opposite sides of a patient. The gantry may include a steel truss (not shown) that is connected to each of its legs, that is long enough to span a treatment area in which the patient lies, and that is attached at both ends to the rotating legs of the gantry. The particle accelerator may be supported by the steel truss for motion around the patient.

In the example of FIGS. 26 and 27 , the patient is located on a treatment couch 1084. In this example, treatment couch 1084 includes a platform that supports the patient. The platform also may include one or more restraints (not shown) for holding the patient in place and for keeping the patient substantially immobile during movement of the couch and during treatment. The platform may, or may not, be padded and/or have a shape (e.g., an indentation) that corresponds to the shape of part of the patient. The couch may be moved via arm 1085.

FIG. 28 shows an example of the gantry configuration described in U.S. Pat. No. 7,728,311 incorporated herein by reference, and includes components of an alternative implementation of a proton therapy system that usable to treat columns of an irradiation target using ultra-high dose rate radiation in the manner described herein. The example proton therapy system of FIG. 28 includes an inner gantry 1190 having a nozzle 1191, a treatment couch 1192, and a particle accelerator 1193 (e.g., a synchrocyclotron of the type described herein) mounted on an outer gantry 1194 for rotation at least part-way around the patient to deliver radiation to target(s) in the patient. Treatment couch 1192 is controllable in accordance with the treatment plan and configured to rotate and to translate the patient in the manner described herein.

In the example of FIG. 28 , particle accelerator 1193 is also mounted to outer gantry 1194 also to enable linear movement (e.g., translational movement) of the particle accelerator in the directions of arrow 1195 along arms 1196. As also shown in FIG. 28 , the particle accelerator 1193 may be connected to a gimbal 1199 for pivoting motion relative to the gantry. This pivoting motion may be used to position the accelerator, and thus the beam, for treatment.

Components of the scanning system including the scanning magnet, the ion chamber, the range modulator, and the configurable collimator may be mounted on, in, or coupled to a nozzle 1081, 1191 of the proton therapy system's inner gantry. These components may be controlled by the control system in accordance with the treatment plan to treat columns of an irradiation target using ultra-high dose rate radiation. In both examples, the nozzle is movable along a track of the inner gantry (1080 or 1190) relative to the patient and the particle accelerator, and is extensible towards, and retractable away from, the patient, thereby also extending and retracting the components mounted thereon.

In some implementations, the synchrocyclotron used in the proton therapy system described herein may be a variable-energy synchrocyclotron. In some implementations, a variable-energy synchrocyclotron is configured to vary the energy of the output particle beam by varying the magnetic field in which the particle beam is accelerated. For example, the current may be set to any one of multiple values to produce a corresponding magnetic field. In an example implementation, one or more sets of superconducting coils receives variable electrical current to produce a variable magnetic field in the cavity. In some examples, one set of coils receives a fixed electrical current, while one or more other sets of coils receives a variable current so that the total current received by the coil sets varies. In some implementations, all sets of coils are superconducting. In some implementations, some sets of coils, such as the set for the fixed electrical current, are superconducting, while other sets of coils, such as the one or more sets for the variable current, are non-superconducting (e.g., copper) coils.

Generally, in a variable-energy synchrocyclotron, the magnitude of the magnetic field is scalable with the magnitude of the electrical current. Adjusting the total electric current of the coils in a predetermined range can generate a magnetic field that varies in a corresponding, predetermined range. In some examples, a continuous adjustment of the electrical current can lead to a continuous variation of the magnetic field and a continuous variation of the output beam energy. Alternatively, when the electrical current applied to the coils is adjusted in a non-continuous, step-wise manner, the magnetic field and the output beam energy also varies accordingly in a non-continuous (step-wise) manner. The scaling of the magnetic field to the current can allow the variation of the beam energy to be carried out relatively precisely, thus reducing the need for an energy degrader. An example of a variable-energy synchrocyclotron that may be used in the particle therapy systems described herein is described in U.S. Pat. No. 9,730,308 entitled “Particle Accelerator That Produces Charged Particles Having Variable Energies”, the contents of which are incorporated herein by reference.

In implementations of the particle therapy system that use a variable-energy synchrocyclotron, controlling the energy of the particle beam to treat a column of the target may be performed in accordance with the treatment plan by changing the energy of the particle beam output by the synchrocyclotron. In such implementations, a range modulator may or may not be used. For example, controlling the energy of the particle beam may include setting the current in the synchrocyclotron main coils to one of multiple values, each which corresponds to a different energy at which the particle beam is output from the synchrocyclotron. A range modulator may be used along with a variable-energy synchrocyclotron to provide additional changes in energy, for, example, between discrete energy levels provided by the synchrocyclotron.

In some implementations, a particle accelerator other than a synchrocyclotron may be used in the particle therapy system described herein. For example, a cyclotron, a synchrotron, a linear accelerator, or the like may be substituted for the synchrocyclotron described herein. Although a rotational gantry has been described (e.g., the outer gantry), the example particle therapy systems described herein are not limited to use with rotational gantries. Rather, a particle accelerator may be mounted, as appropriate, on any type of robotic or other controllable mechanism(s)—characterized herein also as types of gantries—to implement movement of the particle accelerator. For example, the particle accelerator may be mounted on or more robotic arms to implement rotational, pivotal, and/or translational movement of the accelerator relative to the patient. In some implementations, the particle accelerator may be mounted on a track, and movement along the track may be computer-controlled. In this configuration, rotational and/or translational and/or pivotal movement of the accelerator relative to the patient can also be achieved through appropriate computer control. In some implementations, the particle accelerator may be stationary and located outside the treatment room, with the beam being delivered to a nozzle in the treatment room.

In some examples, as noted above, ultra-high dose rates of radiation may include doses of radiation that exceed 1 Gray-per-second for a duration of less than 500 ms. In some examples, ultra-high dose rates of radiation may include doses of radiation that exceed 1 Gray-per-second for a duration that is between 10 ms and 5 s. In some examples, ultra-high dose rates of radiation may include doses of radiation that exceed 1 Gray-per-second for a duration that is less than 5 s.

In some examples, ultra-high dose rates of radiation include doses of radiation that exceed one of the following doses for a duration of less than 500 ms: 2 Gray-per-second, 3 Gray-per-second, 4 Gray-per-second, 5 Gray-per-second, 6 Gray-per-second, 7 Gray-per-second, 8 Gray-per-second, 9 Gray-per-second, 10 Gray-per-second, 11 Gray-per-second, 12 Gray-per-second, 13 Gray-per-second, 14 Gray-per-second, 15 Gray-per-second, 16 Gray-per-second, 17 Gray-per-second, 18 Gray-per-second, 19 Gray-per-second, 20 Gray-per-second, 30 Gray-per-second, 40 Gray-per-second, 50 Gray-per-second, 60 Gray-per-second, 70 Gray-per-second, 80 Gray-per-second, 90 Gray-per-second, or 100 Gray-per-second. In some examples, ultra-high dose rates of radiation include doses of radiation that exceed one of the following doses for a duration that is between 10 ms and 5 s: 2 Gray-per-second, 3 Gray-per-second, 4 Gray-per-second, 5 Gray-per-second, 6 Gray-per-second, 7 Gray-per-second, 8 Gray-per-second, 9 Gray-per-second, 10 Gray-per-second, 11 Gray-per-second, 12 Gray-per-second, 13 Gray-per-second, 14 Gray-per-second, 15 Gray-per-second, 16 Gray-per-second, 17 Gray-per-second, 18 Gray-per-second, 19 Gray-per-second, 20 Gray-per-second, Gray-per-second, 40 Gray-per-second, 50 Gray-per-second, 60 Gray-per-second, 70 Gray-per-second, 80 Gray-per-second, 90 Gray-per-second, or 100 Gray-per-second. In some examples, ultra-high dose rates of radiation include doses of radiation that exceed one of the following doses for a duration that is less than 5 s: 2 Gray-per-second, 3 Gray-per-second, 4 Gray-per-second, 5 Gray-per-second, 6 Gray-per-second, 7 Gray-per-second, 8 Gray-per-second, 9 Gray-per-second, 10 Gray-per-second, 11 Gray-per-second, 12 Gray-per-second, 13 Gray-per-second, 14 Gray-per-second, 15 Gray-per-second, 16 Gray-per-second, 17 Gray-per-second, 18 Gray-per-second, 19 Gray-per-second, 20 Gray-per-second, Gray-per-second, 40 Gray-per-second, 50 Gray-per-second, 60 Gray-per-second, 70 Gray-per-second, 80 Gray-per-second, 90 Gray-per-second, or 100 Gray-per-second.

In some examples, ultra-high dose rates of radiation include doses of radiation that exceed one or more of the following doses for a duration of less than 500 ms, for a duration that is between 10 ms and 5 s, or for a duration that is less than 100 Gray-per-second, 200 Gray-per-second, 300 Gray-per-second, 400 Gray-per-second, or 500 Gray-per-second.

In some examples, ultra-high dose rates of radiation include doses of radiation that are between 20 Gray-per-second and 100 Gray-per-second for a duration of less than 500 ms. In some examples, ultra-high dose rates of radiation include doses of radiation that are between 20 Gray-per-second and 100 Gray-per-second for a duration that is between 10 ms and 5 s. In some examples, ultra-high dose rates of radiation include doses of radiation that are between 20 Gray-per-second and 100 Gray-per-second for a duration that is less than 5 s. In some examples, ultra-high dose rate rates of radiation include doses of radiation that are between 40 Gray-per-second and 120 Gray-per-second for a time period such as less than 5 s. Other examples of the time period are those provided above.

Operation of the example proton therapy systems described herein, and operation of all or some component thereof, can be controlled (as appropriate), at least in part, using one or more computer program products, e.g., one or more computer programs tangibly embodied in one or more non-transitory machine-readable media, for execution by, or to control the operation of, one or more data processing apparatus, e.g., a programmable processor, a computer, multiple computers, and/or programmable logic components.

A computer program can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. A computer program can be deployed to be executed on one computer or on multiple computers at one site or distributed across multiple sites and interconnected by a network.

Actions associated with controlling all or part of the operations of the example proton therapy systems described herein can be performed by one or more programmable processors executing one or more computer programs to perform the functions described herein. All or part of the operations can be controlled using special purpose logic circuitry, e.g., an FPGA (field programmable gate array) and/or an ASIC (application-specific integrated circuit).

Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any kind of digital computer. Generally, a processor will receive instructions and data from a read-only storage area or a random access storage area or both. Elements of a computer (including a server) include one or more processors for executing instructions and one or more storage area devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from, or transfer data to, or both, one or more machine-readable storage media for storing data, e.g., magnetic, magneto-optical disks, or optical disks. Non-transitory machine-readable storage media suitable for storing computer program instructions and data include all forms of non-volatile storage area, including by way of example, semiconductor storage area devices, e.g., EPROM, EEPROM, and flash storage area devices; magnetic disks, e.g., internal hard disks or removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks.

Any two more of the foregoing implementations may be used in an appropriate combination with an appropriate particle accelerator (e.g., a synchrocyclotron). Likewise, individual features of any two more of the foregoing implementations may be used in an appropriate combination. Elements may be left out of the processes, systems, apparatus, etc., described herein without adversely affecting their operation. Various separate elements may be combined into one or more individual elements to perform the functions described herein. 

What is claimed is: 1-41. (canceled)
 41. One or more non-transitory machine-readable storage media storing instructions that are executable to implement a treatment planning system for a particle therapy system, the treatment planning system comprising: a prediction model that characterizes the particle therapy system and a patient to be treated by the particle therapy system, the prediction model characterizing the particle therapy system at least in part by characterizing a timing at which the particle therapy system can deliver radiation; a relative biological effectiveness (RBE) model that characterizes a relative biological effectiveness of the radiation on tissue based on the timing of delivery of the radiation; and a dose calculation engine to determine a dose regimen for delivery of the radiation to voxels of the patient, the dose calculation engine being configured to determine the dose regimen based on the prediction model and the RBE model.
 42. The one or more non-transitory machine-readable storage media of claim 41, wherein the dose regimen specifies doses and dose rates at which the radiation is to be delivered to the voxels; and wherein the treatment planning system further comprises a sequencer to generate instructions for sequencing delivery of doses in order to optimize effective doses determined by the dose calculation engine.
 43. The one or more non-transitory machine-readable storage media of claim 41, wherein the prediction model characterizes the particle therapy system based on a structure of pulses of a particle beam produced by a particle accelerator.
 44. The one or more non-transitory machine-readable storage media of claim 41, wherein the prediction model characterizes the particle therapy system based on a maximum dose per pulse of a particle beam produced by a particle accelerator.
 45. The one or more non-transitory machine-readable storage media of claim 41, wherein the prediction model characterizes the particle therapy system based on a sweep time of a scanning magnet to move a particle beam produced by a particle accelerator.
 46. The one or more non-transitory machine-readable storage media of claim 41, wherein the prediction model characterizes the particle therapy system based on a time it takes to change an energy of a particle beam produced by a particle accelerator.
 47. The one or more non-transitory machine-readable storage media of claim 41, wherein the prediction model characterizes the particle therapy system based on a time it takes to move one or more energy-absorbing structures to change an energy of a particle beam produced by a particle accelerator.
 48. The one or more non-transitory machine-readable storage media of claim 41, wherein the prediction model characterizes the particle therapy system based on a strategy for regulating doses of radiation.
 49. The one or more non-transitory machine-readable storage media of claim 41, wherein the prediction model characterizes the particle therapy system based on a time it takes to move a collimator for collimating a particle beam produced by a particle accelerator.
 50. The one or more non-transitory machine-readable storage media of claim 41, wherein the prediction model characterizes the particle therapy system based on a time it takes to configure a collimator for collimating a particle beam produced by a particle accelerator.
 51. The one or more non-transitory machine-readable storage media of claim 41, wherein the prediction model characterizes the particle therapy system based on a time it takes to control a range modulator to change a Bragg peak of particles in a particle beam produced by a particle accelerator.
 52. The one or more non-transitory machine-readable storage media of claim 41, wherein the dose calculation engine is configured to determine times at which doses specified in the dose regimen are to be delivered to the voxels of the patient based on the RBE model.
 53. The one or more non-transitory machine-readable storage media of claim 41, wherein the dose calculation engine is configured to determine whether a voxel among the voxels contains targeted tissue, non-targeted tissue, or both targeted tissue and non-targeted tissue, and to determine a dose rate of radiation to the voxel based at least in part on whether the voxel contains targeted tissue, non-targeted tissue, or both targeted tissue and non-targeted tissue.
 54. The one or more non-transitory machine-readable storage media of claim 53, wherein the targeted tissue comprises diseased tissue and the non-targeted tissue comprises healthy tissue.
 55. The one or more non-transitory machine-readable storage media of claim 53, wherein, in a case that the voxel contains non-targeted tissue only, determining the dose rate of radiation to the voxel comprises determining to deliver no dose to the voxel.
 56. The one or more non-transitory machine-readable storage media of claim 53, wherein, in a case that the voxel contains targeted tissue or both targeted tissue and non-targeted tissue, determining the dose rate of radiation to the voxel includes determining to deliver ultra-high dose rate radiation to the voxel.
 57. The one or more non-transitory machine-readable storage media of claim 56, wherein the ultra-high dose rate radiation comprises a dose of radiation that exceeds one (1) Gray-per-second for a duration of less than five (5) seconds.
 58. The one or more non-transitory machine-readable storage media of claim 56, wherein the ultra-high dose rate radiation comprises a dose of radiation that exceeds one (1) Gray-per-second for a duration of less than 500 ms.
 59. The one or more non-transitory machine-readable storage media of claim 56, wherein the ultra-high dose rate radiation comprises a dose of radiation that is between 40 Gray-per-second and 120 Gray-per-second for a duration of less than 500 ms.
 60. The one or more non-transitory machine-readable storage media of claim 41, wherein the dose regimen specifies doses and dose rates at which the radiation is to be delivered to the voxels; and wherein the doses are equivalent doses determined based on a weighting factor from the RBE model. 61-106. (canceled) 